Novel nk-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in nk-3 receptors mediated disorders

ABSTRACT

and their use as therapeutic compounds.

This application is a Continuation of PCT international application Ser.No. PCT/EP2011/055218, filed Apr. 4, 2011, designating the UnitedStates, which claims the benefit of European Application No. 10305343.5,filed on Apr. 2, 2010, and also claims the benefit of U.S. ProvisionalApplication 61/379,028, filed Sep. 1, 2010. The entire contents of theaforementioned patent applications are incorporated herein by thisreference.

The present invention relates to novel compounds including theirpharmaceutically acceptable salts and solvates, which are selectiveantagonists of neurokinin 3 receptor (NK-3) and are useful astherapeutic compounds, particularly in the treatment and/or preventionof a broad array of CNS and peripheral diseases or disorders.

BACKGROUND OF THE INVENTION

Tachykinin receptors are the targets of a family of structurally relatedpeptides which include substance P (SP), neurokinin A (NKA) andneurokinin B (NKB), named collectively “tachykinins”. Tachykinins aresynthesized in the central nervous system (CNS) and peripheral tissues,where they exert a variety of biological activities. Three tachykininreceptors are known which are named neurokinin-1 (NK-1), neurokinin-2(NK-2) and neurokinin-3 (NK-3) receptors. Tachykinin receptors belong tothe rhodopsin-like seven membrane G-protein coupled receptors. SP hasthe highest affinity and is believed to be the endogenous ligand ofNK-1, NKA for NK-2 receptor and NKB for NK-3 receptor, although somecrossreactivity probably exists. The NK-1, NK-2 and NK-3 receptors havebeen identified in different species. NK-1 and NK-2 receptors areexpressed in a wide variety of peripheral tissues and NK-1 receptors arealso expressed in the CNS; whereas NK-3 receptors are primarilyexpressed in the CNS.

The neurokinin receptors mediate a variety of tachykinin-stimulatedbiological effects that include transmission of excitatory neuronalsignals in the CNS and periphery (e.g. pain), modulation of smoothmuscle contractile activity, modulation of immune and inflammatoryresponses, induction of hypotensive effects via dilatation of theperipheral vasculature and stimulation of endocrine and exocrine glandsecretions.

In the CNS, the NK-3 receptor is expressed in regions including themedial prefrontal cortex, the hippocampus, the thalamus and theamygdala. Moreover, NK-3 receptors are expressed on dopaminergicneurons. Activation of NK-3 receptors has been shown to modulatedopamine, acetylcholine and serotonin release suggesting a therapeuticutility for NK-3 receptor modulators for the treatment of a variety ofdisorders including psychotic disorders, anxiety, depression,schizophrenia as well as obesity, pain or inflammation (Exp. OpinionTher. Patents (2000), 10(6); 939-960 Current Opinion in InvestigationalDrugs, 2001, 2(7), 950-956 and Current Pharmaceutical Design, 2010, 16,344-357).

Schizophrenia is classified into subgroups. The paranoid type ischaracterized by delusions and hallucinations and absence of thoughtdisorder, disorganized behavior, and affective flattening. In thedisorganized type, which is also named ‘hebephrenic schizophrenia’ inthe International Classification of Diseases (ICD), thought disorder andflat affect are present together. In the catatonic type, prominentpsychomotor disturbances are evident, and symptoms may include catatonicstupor and waxy flexibility. In the undifferentiated type, psychoticsymptoms are present but the criteria for paranoid, disorganized, orcatatonic types have not been met. The symptoms of schizophrenianormally manifest themselves in three broad categories, i.e. positive,negative and cognitive symptoms. Positive symptoms are those, whichrepresent an “excess” of normal experiences, such as hallucinations anddelusions. Negative symptoms are those where the patient suffers from alack of normal experiences, such as anhedonia and lack of socialinteraction. The cognitive symptoms relate to cognitive impairment inschizophrenics, such as a lack of sustained attention and deficits indecision making. The current antipsychotic drugs (APDs) are fairlysuccessful in treating the positive symptoms but fare less well for thenegative and cognitive symptoms. Contrary to that, NK3 antagonists havebeen shown clinically to improve on both positive and negative symptomsin schizophrenics (Meltzer et al, Am. J. Psychiatry, 161, 975-984, 2004)and ameliorate cognitive behavior of schizophrenics (Curr. Opion.Invest. Drug, 6, 717-721, 2005).

In rat, morphological studies provide evidence for putative interactionsbetween NKB neurons and the hypothalamic reproductive axis (Krajewski etal, J. Comp. Neurol., 489(3), 372-386, 2005). In arcuate nucleusneurons, NKB expression co-localizes with estrogen receptor a anddynorphin, implicated in progesterone feedback to Gonadotropin ReleasingHormone (GnRH) secretion (Burke et al., J. Comp. Neurol., 498(5),712-726, 2006; Goodman et al., Endocrinology, 145, 2959-2967, 2004).Moreover, NK-3 receptor is highly expressed in the hypothalamic arcuatenucleus in neurons which are involved in the regulation of GnRH release.

WO 00/43008 discloses a method of suppressing gonadotropin and/orandrogen production with specific NK-3 receptor antagonists. Moreparticularly, the WO 00/43008 application relates to loweringluteinizing hormone (LH) blood level by administering an NK-3 receptorantagonist. Concurently or alternatively with gonadotropin suppression,WO 00/43008 also relates to suppression of androgen production with NK-3receptor antagonists. Recently it has been postulated that NKB actsautosynaptically on kisspeptin neurons in the arcuate nucleus tosynchronize and shape the pulsatile secretion of kisspeptin and drivethe release of GnRH from fibers in the median eminence (Navarro et al.,J. of Neuroscience, 23, 2009—pp 11859-11866). All these observationssuggest a therapeutic utility for NK-3 receptor modulators for sexhormone-dependent diseases.

Non-peptide ligands have been developed for each of the tachykininreceptors.

Some of them have been described as dual modulators able to modulateboth NK-2 and NK-3 receptors (WO 06/120478). However known non-peptideNK-3 receptor antagonists suffer from a number of limitations such aspoor drug bioavailability, poor CNS penetration and weak potencyparticularly at mouse/rat ortholog receptors, all aspects which limitthe potential to evaluate these compounds in preclinical models and/orclinical development. On this basis, new potent and selectiveantagonists of NK-3 receptor may be of therapeutic value for thepreparation of drugs useful in the treatment and/or prevention of CNSand peripheral diseases or disorders in which NKB and the NK-3 receptorsare involved.

SUMMARY OF THE INVENTION

The invention encompasses compounds of general Formula I, theirpharmaceutically acceptable salts and solvates as well as methods of useof such compounds or compositions comprising such compounds asantagonists of NK-3 receptor activity.

In a general aspect, the invention provides compounds of general formulaI:

and pharmaceutically acceptable salts and solvates thereof, whereinAr¹ is a 5- to 6-membered aryl or heteroaryl group, 3- to 6-memberedcycloalkyl group a 3- to 6-membered heterocyclyl group or a C3-C6 alkylgroup, each of the aryl, heteroaryl, cycloalkyl or heterocyclyl groupsbeing optionally substituted by one or more group(s) selected from halo,cyano, alkyl, haloalkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl,aralkyl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, alkoxyalkoxy,alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl,carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino,or two substituents form an alkylenedioxy group or a haloalkylenedioxygroup, or two substituents form a cycloalkyl or heterocycloalkyl moietytogether with the cycloalkyl or heterocycloalkyl group they are attachedto, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkylgroup may be one or more aryl moiety, each of said substituents beingoptionally substituted by one or more further substituent(s) selectedfrom halo, cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy,heterocyclyl, aryl, heteroaryl, aryloxy or heteroaryloxy;L is C₁-C₂ alkylene optionally being substituted by one or more group(s)selected from halo, methyl or ethyl under the condition that R^(2′)together with R² form an oxo substituent, or L¹ is carbonyl or sulfonyl,or L¹ is —(C═O)—CH₂— where the C═O is linked to the piperazine nitrogenand the CH₂ to Ar¹;R¹ is H, a C₁-C₄ alkyl, aryl or aralkyl group, each of said alkyl, arylor aralkyl groups being optionally substituted by one or more group(s)selected from halo or hydroxyl;R^(1′) is H or a C₁-C₄ alkyl group;R² is H or a C₁-C₄ alkyl group;R^(2′) is H or a C₁-C₄ alkyl group, or, when L¹ is C₁-C₂ alkyleneoptionally being substituted by one or more group(s) selected from halo,methyl or ethyl, R^(2′) together with R² form an oxo substituent;R³ is H or a C₁-C₄ alkyl group optionally substituted by one hydroxy;R^(3′) is H or a C₁-C₄ alkyl group;X¹ and X² are independently selected from N or C—Z wherein Z is H orC₁-C₂ alkyl under the condition that X¹ and X² cannot be both C—Z;L² is a single bond or carbonyl;Ar² is a 5- to 6-membered aryl or heteroaryl group, each of the aryl, orheteroaryl groups being optionally substituted by one or more group(s)selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,hydroxyl, alkoxy, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl,alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, acylamino,carbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino,alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,arylsulfonylalkyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,haloalkylsulfonylamino, or two substituents form an alkylenedioxy groupor a haloalkylenedioxy group, or fused to the aryl or heteroaryl groupmay be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety,each of said substituents being optionally substituted by one or morefurther substituent(s) selected from halo, cyano, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, heterocyclyl optionally substituted byalkyl, aryl, heteroaryl, hydroxyl, alkoxyalkyl, hydroxyalkoxy,alkylamino, alkylsulfonylamino, alkoxycarbonylamino, aminoalkoxy, oralkoxycarbonylaminoalkoxy;and wherein, when:R¹, R^(1′), R², R^(2′), R³, R^(3′) are H, andL¹ is carbonyl, andL² is single bond, and

X² is N, and

Ar¹ is a 6-membered aryl optionally substituted by one or more group(s)selected from halo, cyano, C1-C3 alkyl, C1 haloalkyl, andAr² is a 5- to 6-membered aryl or heteroaryl group optionallysubstituted by one or more group(s) selected from halo, C1-C3 alkyl,hydroxyl, methoxy, or fused to an aryl or heteroaryl group optionallysubstituted by one or more further halo, C1-C3 alkyl, hydroxyl, methoxy,then,Ar¹ is phenyl, 3-halophenyl, 4-halophenyl, 2,3-dichlorophenyl,2,4-difluorophenyl, 2,4-dichlorophenyl, 2,5-dihalophenyl,2,6-difluorophenyl, 2,6-dichlorophenyl, 3,4-dihalophenyl,3,5-dihalophenyl, 3,4,5-trihalophenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 2,3-dicyanophenyl, 2,4-dicyanophenyl, 3,5-dicyanophenyl,3-cyano-4-halophenyl, 4-(C1-C3 alkyl)phenyl, 3,4-di(C1-C3 alkyl)phenyl,3,5-di(C1-C3 alkyl)phenyl, 4-(C1 haloalkyl)phenyl, andAr² is 2-(C1-C3 alkyl)thiazol-4-yl, 5-(C1-C3 alkyl)thiazol-4-yl,pyridin-2-yl, 4-halopyridin-2-yl, 4-(C1-C3 alkyl)pyridin-2-yl, 5-(C1-C3alkyl)pyridin-2-yl, 6-(C1-C3 alkyl)pyridin-2-yl, quinolin-2-yl,isoquinolin-3-yl, 8-haloquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl;with the following provisos:

-   -   compounds wherein L¹ is CO, L² is a single bond, X¹ is N, X² is        CH and Ar² is a substituted phenyl are excluded; and    -   Ar¹ is neither a substituted or unsubstituted        pyrazolo[1,5-a]pyridin-2yl nor a substituted or unsubstituted        pyrazolo[1,5-a]pyrimidin-2yl moiety; and        the compound of formula I is none of:

-   1-methyl-7-[(3-phenyl-5-isoxazolyl)carbonyl]-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   7-[(2-benzyl-1,3-thiazol-4-yl)carbonyl]-1-methyl-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   3-{[1-methyl-3-(1-phenyl-1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]carbonyl}-1-indanone,

-   7-[5-(4-methoxyphenyl)-2-furoyl]-1-methyl-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   1-methyl-3-(4-pyridinyl)-7-(4,5,6,7-tetrahydro-1-benzothien-3-ylcarbonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   2-{2-[1-methyl-3-(2-methyl-1,3-thiazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]-2-oxoethyl}-1,2,3,4-tetrahydroisoquinoline,

-   7-[(1,3-diphenyl-1H-pyrazol-5-yl)carbonyl]-1-methyl-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   8-fluoro-2-{[1-methyl-3-(4-pyridinyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]carbonyl}quinoline,

-   1-methyl-3-(2-methyl-1,3-thiazol-4-yl)-7-{[2-(2-thienyl)-1,3-thiazol-4-yl]carbonyl}-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   7-(3-fluoro-4-methoxybenzoyl)-1-methyl-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   7-[(3-ethyl-5-methyl-4-isoxazolyl)carbonyl]-1-methyl-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   3-{2-[1-methyl-3-(1-phenyl-1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]-2-oxoethyl}-4(3H)-quinazolinone,

-   3-{[1-methyl-3-(1-phenyl-1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]carbonyl}-6,7-dihydro-1-benzofuran-4(5H)-one,

-   7-{[3-(2-methoxyphenyl)-1H-pyrazol-5-yl]carbonyl}-1-methyl-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   3-{[1-methyl-3-(1-phenyl-1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]carbonyl}-4H-pyrido[1,2-a]pyrimidin-4-one,

-   1-ethyl-3-(2-methoxyphenyl)-7-[3-(1H-pyrazol-1-yl)benzoyl]-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   1-methyl-7-[(3-phenyl-1-piperidinyl)acetyl]-3-(4-pyridinyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   1-methyl-3-(2-methyl-1,3-thiazol-4-yl)-7-(1,2,5-thiadiazol-3-ylcarbonyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine,

-   (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)(1-methyl-3-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone,

-   3-(1-methyl-3-(pyridin-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-5,6,7,8-tetrahydroquinolin-2(1H)-one,

-   (2,3-dihydrobenzofuran-2-yl)(1-methyl-3-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone,

-   (1-methyl-3-(1-phenyl-1H-pyrazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(8-methylimidazo[1,2-a]pyridin-2-yl)methanone,

-   (2,3-dihydrothieno[3,4-b][1,4]dioxin-5-yl)(1-methyl-3-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone,

-   2-methyl-6-(1-methyl-3-(pyridin-4-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-7-carbonyl)-4,5-dihydropyridazin-3(2H)-one

-   (3-(2-methoxyphenyl)-1H-pyrazol-5-yl)(1-methyl-3-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone,

-   (2,3-dihydrobenzofuran-2-yl)(1-methyl-3-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone,

-   (1-methyl-3-(2-methylthiazol-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(2-(thiophen-2-yl)thiazol-4-yl)methanone,

-   (3,5-dimethyl-1H-pyrrol-2-yl)(1-methyl-3-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone,

-   (1-methyl-3-(pyridin-4-yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)methanone;

-   (2,4-dichlorophenyl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

-   (2,4-difluorophenyl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

-   (3-chlorophenyl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;

-   2-(3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)benzonitrile;

-   (2,6-dichlorophenyl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone,

-   (2,3-dichlorophenyl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone,

-   (2,3-dichlorophenyl)(3-(5-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone,

-   (2,3-dichlorophenyl)(3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising at least one compound according to the inventionor a pharmaceutically acceptable salt or solvate thereof.

The invention also relates to the use of the above compounds or theirpharmaceutically acceptable salts and solvates as modulators of NK-3receptors, preferably as antagonists of NK-3 receptors.

The invention further provides methods of treatment and/or prevention ofdepression, anxiety, pyschosis, schizophrenia, psychotic disorders,bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer'sdisease, attention deficit hyperactivity disorder (ADHD), pain,convulsion, obesity, inflammatory diseases including irritable bowelsyndrome and inflammatory bowel disorders, emesis, pre-eclampsia, airwayrelated diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders and sex hormone-dependent diseases including butnot limited to benign prostatic hyperplasia (BPH), metastatic prostaticcarninoma, testicular cancer, breast cancer, androgen dependent acne,male pattern baldness, endometriosis, abnormal puberty, uterinefibrosis, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome(hyperandrogenism, insulin resistance and acanthosis nigricans), ovarianhyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells inovarian stroma), other manifestations of high intraovarian androgenconcentrations (e.g. follicular maturation arrest, atresia, anovulation,dysmenorrhea, dysfunctional uterine bleeding, infertility) andandrogen-producing tumor (virilizing ovarian or adrenal tumor)comprising the administration of a therapeutically effective amount of acompound or pharmaceutically acceptable salt or solvate of formula (I),to a patient in need thereof. Preferably the patient is a warm-bloodedanimal, more preferably a human.

The invention further provides methods of treatment for gynecologicaldisorders and infertility. In particular, the invention provides methodsto suppress the LH-surge in assisted conception comprising theadministration of a therapeutically effective amount of a compound orpharmaceutically acceptable salt or solvate of formula (I), to a patientin need thereof. Preferably the patient is a warm-blooded animal, morepreferably a woman.

The invention further provides methods to affect androgen production tocause male castration and to inhibit the sex drive in male sexualoffenders comprising the administration of a therapeutically effectiveamount of a compound or pharmaceutically acceptable salt or solvate offormula (I), to a patient in need thereof. Preferably the patient is awarm-blooded animal, more preferably a man.

The invention also provides the use of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as a medicament.Preferably, the medicament is used for the treatment and/or preventionof depression, anxiety, pyschosis, schizophrenia, psychotic disorders,bipolar disorders, cognitive disorders, Parkinson's disease, Alzheimer'sdisease, attention deficit hyperactivity disorder (ADHD), pain,convulsion, obesity, inflammatory diseases including irritable bowelsyndrome and inflammatory bowel disorders, emesis, pre-eclampsia, airwayrelated diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders and sex hormone-dependent diseases including butnot limited to benign prostatic hyperplasia (BPH), metastatic prostaticcarninoma, testicular cancer, breast cancer, androgen dependent acne,male pattern baldness, endometriosis, abnormal puberty, uterinefibrosis, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome(hyperandrogenism, insulin resistance and acanthosis nigricans), ovarianhyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells inovarian stroma), other manifestations of high intraovarian androgenconcentrations (e.g. follicular maturation arrest, atresia, anovulation,dysmenorrhea, dysfunctional uterine bleeding, infertility) andandrogen-producing tumor (virilizing ovarian or adrenal tumor). Themedicament may also be used for the treatment of gynecologic disorder,infertility and to affect androgen production to cause male castration.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the invention relates to compounds of formula I, as wellas their pharmaceutically acceptable salts and solvates.

Preferred compounds of formula I and pharmaceutically acceptable saltsand solvates thereof are those wherein

Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 5- to 6-memberedcycloalkyl group, C3-C6 alkyl group, each of the aryl or heteroarylgroups being optionally substituted by one or more group(s) selectedfrom halo, cyano, alkyl, haloalkyl, C3-C6 cycloalkyl, heteroalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy,alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl,carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino,or two substituents form an alkylenedioxy group or a haloalkylenedioxygroup, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkylgroup may be one aryl moiety, each of said substituents being optionallysubstituted by one or more further substituent(s) selected from halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy, heterocyclyl,aryl, heteroaryl, aryloxy or heteroaryloxy, preferably Ar¹ is a 5- to6-membered aryl, preferably phenyl, heteroaryl group preferablypyridinyl, isopropyl, isobutyl, each of the aryl or heteroaryl groupsbeing optionally substituted by one or more group(s) selected from halo,cyano, alkyl, haloalkyl, C3-C6 cycloalkyl, aryl, heteroaryl, or fused tothe aryl or heteroaryl group may be one aryl, preferably phenyl, moiety,each of said substituents being optionally substituted by one or morefurther substituent(s) selected from halo, alkyl, haloalkyl,cyclopropyl, haloalkoxy, or aryloxy, more preferably Ar¹ is a phenyl, abiaryl, preferably 4-biphenyl, heterobiaryl preferably4-(thiophen-2-yl)phenyl, 3-phenyl-1H-pyrazol-5-yl, 5-phenylpyridin-2-yl,2-phenylpyridin-5-yl, more preferably 4-(thiophen-2-yl)phenyl, each ofsaid biaryl or heterobiaryl being optionally substituted by one or morefurther substituent(s) selected from halo, alkyl, cyclopropyl,haloalkyl, haloalkoxy or aryloxy; and/orL¹ is carbonyl; and/orR¹ is H, a C₁-C₄ alkyl, aryl or aralkyl group, each of said alkyl, arylor aralkyl groups being optionally substituted by one or more group(s)selected from halo or hydroxyl, preferably R¹ is H, a C₁-C₃ alkyl,preferably methyl or isopropyl, hydroxyethyl, phenyl or benzyl group,each of said phenyl or benzyl groups being optionally substituted by oneor more group(s) selected from halo, preferably fluoro or chloro, morepreferably R¹ is H, methyl or 2-hydroxyethyl; and/orR^(1′) is H or methyl preferably R^(1′) is H; and/orR², R^(2′), R³ and R^(3′) are H; and/orX¹ and X² are independently selected from N or C—Z wherein Z is H ormethyl, under the condition that X¹ and X² cannot be both C—Z,preferably X¹ and X² are independently selected from N or CH under thecondition that X¹ and X² cannot be both CH, more preferably X¹ and X²are both N; and/orL² is a single bond; and/orAr² is a 5- to 6-membered heteroaryl group optionally substituted by oneor more group(s) selected from halo, cyano, alkyl, haloalkyl, C3-C6cycloalkyl heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,arylsulfonylalkyl, alkoxy, or fused to the heteroaryl group may be onecycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,alkoxy, heterocyclyl optionally substituted by alkyl aryl, hydroxyl,alkoxyalkyl, hydroxyalkoxy, alkylamino, alkylsulfonylamino,alkoxycarbonylamino, aminoalkoxy, or alkoxycarbonylaminoalkoxypreferably Ar² is a fused heteroaryl, preferably quinolin-2-yl,benzo[d]thiazol-2-yl, 4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl,heterocyclylheteroaryl, preferably 2-(pyrrolidin-1-yl)thiazol-4-yl,2-(piperidin-1-yl)thiazol-4-yl, 2-(morpholin-4-yl)thiazol-4-yl,2-(piperazin-1-yl)thiazol-4-yl, heterobiaryl preferably2-phenylthiazol-4-yl, 2-phenyloxazol-4-yl, 2-phenylthiazol-5-yl,2-phenyloxazol-5-yl, 2-phenylimidazol-4-yl, 3-phenylpyrazol-5-yl,5-phenylpyrazol-3-yl, 3-phenyl-1,2,4-oxadiazol-5-yl,3-phenyl-1,2,4-thiadiazol-5-yl, 5-phenyl-1,2,4-oxadiazol-3-yl,5-phenyl-1,2,4-triazol-3-yl, 2-(thiophen-2-yl)thiazol-4-yl,2-(pyridin-2-yl)thiazol-4-yl, 2-(pyridin-4-yl)thiazol-4-yl,2-(quinolin-2-yl)thiazol-4-yl, 2-(pyrazin-2-yl)thiazol-4-yl, each ofsaid fused heteroaryl, heterocyclylheteroaryl and heterobiaryl beingoptionally substituted by one or more further substituent(s) selectedfrom halo, cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, heterocyclyloptionally substituted by alkyl, aryl, hydroxyl, alkoxyalkyl,hydroxyalkoxy, alkylamino, alkylsulfonylamino, aminoalkoxy, oralkoxycarbonylaminoalkoxy; and/orwherein, when:R¹, R^(1′), R², R^(2′), R³, R^(3′) are H, andL¹ is carbonyl, andL² is single bond, and

X² is N, and

Ar¹ is a 6-membered aryl optionally substituted by one or more group(s)selected from halo, cyano, C1-C3 alkyl, C1 haloalkyl, andAr² is a 5- to 6-membered aryl or heteroaryl group optionallysubstituted by one or more group(s) selected from halo, C1-C3 alkyl,hydroxyl, methoxy, or fused to an aryl or heteroaryl group optionallysubstituted by one or more further halo, C1-C3 alkyl, hydroxyl, methoxy,then,Ar¹ is phenyl, 3-halophenyl, 4-halophenyl, 2,3-dichlorophenyl3,4-dihalophenyl, 3,4,5-trihalophenyl, 4-cyanophenyl, 4-(C1-C3alkyl)phenyl, 4-(C1 haloalkyl)phenyl, preferably Ar¹ is phenyl,3-fluorophenyl, 3-chlorophenyl, 4-fluorophenyl, 4-chlorophenyl,3,4-difluorophenyl, 3,4-dichlorophenyl, 4-chloro-3-fluorophenyl,3-chloro-4-fluorophenyl, 3,4,5-trifluorophenyl, 4-cyanophenyl, 4-tolyl,4-trifluoromethylphenyl, andAr² is 2-(C1-C3 alkyl)thiazol-4-yl, 5-(C1-C3 alkyl)thiazol-4-yl,pyridin-2-yl, 4-halopyridin-2-yl, 4-(C1-C3 alkyl)pyridin-2-yl, 5-(C1-C3alkyl)pyridin-2-yl, 6-(C1-C3 alkyl)pyridin-2-yl, quinolin-2-yl,isoquinolin-3-yl, 8-haloquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, preferably, Ar² is2-isopropylthiazol-4-yl, 5-methylthiazol-4-yl, pyridin-2-yl,4-chloropyridin-2-yl, 4-methylpyridin-2-yl, 5-methylpyridin-2-yl,6-methylpyridin-2-yl, quinolin-2-yl, isoquinolin-3-yl,8-fluoroquinolin-2-yl, 8-chloroquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl.

In one embodiment, preferred compounds of Formula I are those of formulaIa:

and pharmaceutically acceptable salts and solvates thereof, whereinAr¹, Ar², L¹, R¹, R^(1′), R², R^(2′), R³, R^(3′), X¹ and X² are asdefined above in respect to formula I.

Preferred compounds of formula Ia are those of formula Ib:

and pharmaceutically acceptable salts and solvates thereof, whereinAr¹ is as defined above in respect to formula I, preferably Ar¹ is a 5-to 6-membered aryl or heteroaryl group, 5- to 6-membered cycloalkylgroup, or a C3-C6 alkyl group each of the aryl, heteroaryl or cycloalkylgroups being optionally substituted by one or more group(s) selectedfrom halo, cyano, alkyl, haloalkyl, 3- to 6-membered cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, alkoxy, haloalkoxy,alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, carbamoyl, alkylcarbamoyl, alkylsulfonyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, or two substituents form analkylenedioxy group, or fused to the aryl or heteroaryl group may be oneor more aryl moiety, each of said substituents being optionallysubstituted by one or more further substituent(s) selected from halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy, heterocyclyl,aryloxy or heteroaryloxy, more preferably Ar¹ is a 5- to 6-membered arylgroup preferably phenyl, or 5- to 6-membered heteroaryl group preferablypyrazolyl, pyridinyl, more preferably pyrazolyl, C3-C6 alkyl group, eachof the aryl or heteroaryl group being optionally substituted by one ormore group(s) selected from halo, cyano, alkyl, haloalkyl, C3-C6cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, alkoxy,haloalkoxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, carbamoyl, alkylcarbamoyl, alkylsulfonyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, or two substituents form analkylenedioxy group, or fused to the aryl or heteroaryl group may be onearyl moiety, each of said substituents being optionally substituted byone or more further substituent(s) selected from halo, cyano, alkyl,haloalkyl, cyclopropyl, alkoxy, haloalkoxy, heterocyclyl, aryloxy, orheteroaryloxy, even more preferably Ar¹ is a 5- to 6-membered arylpreferably phenyl, or heteroaryl preferably pyrrolyl, oxazolyl,thiazolyl, pyrazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl,pyrimidinyl, pyrazinyl, pyridazinyl, more preferably pyrazolyl group,isobutyl, each of the aryl or heteroaryl groups being optionallysubstituted by one or more group(s) selected from halo preferably chloroor fluoro, cyano, alkyl preferably methyl, haloalkyl preferably —CF₃ or—CHF₂, cycloalkyl preferably cyclopropyl, cyclohexyl, aryl preferablyphenyl, heteroaryl preferably furanyl, thiophenyl, thiazolyl,isothiazolyl, more preferably thiophen-2-yl, thiophen-3-yl,thiazol-2-yl, thiazol-5-yl, isothiazol-5-yl, even more preferablythiophen-2-yl, thiophen-2-yl, furan-2-yl, or fused to the aryl orheteroaryl group may be one phenyl moiety, each of said substituentsbeing optionally substituted by one or more further substituent(s)selected from halo preferably chloro or fluoro, alkyl preferably methyl,haloalkyl preferably —CF₃ or —CHF₂, cyclopropyl, haloalkoxy preferably—OCF₃ or —OCHF₂, or aryloxy preferably phenoxy; andR¹ is as defined above in respect to formula I, preferably R¹ is H,C₁-C₄ alkyl preferably isopropyl, methyl, aryl preferably phenyl, oraralkyl preferably benzyl, each of which being optionally substituted byone or more group(s) selected from halo, preferably chloro, fluoro, orhydroxyl, more preferably R¹ is H, methyl, isopropyl, 2-hydroxyethyl,4-fluorophenyl or benzyl, still more preferably R¹ is H, methyl or2-hydroxyethyl, even more preferably R¹ is methyl; andR^(1′) is as defined above in respect to formula I, preferably R^(1′) isH or methyl, more preferably R^(1′) is H;R², R^(2′), R³ and R^(3′) are as defined above in respect to formula I,preferably R², R^(2′), R³ and R^(3′) are H; andX¹ and X² are as defined above in respect to formula I, preferably X¹and X² are independently selected from N or C—Z wherein Z is H or methylunder the condition that X¹ and X² cannot be both C—Z, more preferablyX¹ and X² are independently selected from N or CH under the conditionthat X¹ and X² cannot be both CH, even more preferably X¹ and X² are N;andAr² is as defined above in respect to formula I, preferably, Ar² is a 5-to 6-membered heteroaryl group optionally substituted by one or moregroup(s) selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl,C3-C6 cycloalkyl, heteroalkyl, heterocyclyl, aryl, aralkyl, heteroaryl,heteroarylalkyl, hydroxyl, alkoxy, alkylamino, carboxy, alkoxycarbonyl,alkylcarbonyloxy, alkylcarbonylamino, acylamino, carbamoyl,alkylcarbamoyl, alkylsulfonyl, arylsulfonylalkyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, or two substituents form analkylenedioxy group, or fused to the heteroaryl group may be one or morecycloalkyl, aryl, heterocyclyl or heteroaryl moiety, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,alkoxy, haloalkoxy, alkoxyalkyl, cycloalkyl, aryl, heterocyclyloptionally substituted by alkyl, heteroaryl, hydroxyl, alkoxy,alkoxyalkyl, hydroxyalkoxy, alkylamino, alkylsulfonylamino,alkoxycarbonylamino, aminoalkoxy or alkoxycarbonylaminoalkoxy, morepreferably Ar² is a 5- to 6-membered heteroaryl preferably imidazolyl,pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, thiadiazolyl orpyridyl group, each of the heteroaryl groups being optionallysubstituted by one or more group(s) selected from halo preferably chloroor fluoro, cyano, alkyl preferably methyl, isopropyl, isobutyl,haloalkyl preferably —CF₃ or —CHF₂, C3-C6 cycloalkyl preferablycyclopropyl, heterocyclyl preferably pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, aryl preferably phenyl, aralkyl preferablybenzyl, heteroarylalkyl preferably (imidazol-3-yl)methyl,arylsulfonylalkyl preferably phenylsulfonylmethyl, heteroaryl preferablythiophen-2-yl, pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyrazin-2-yl,quinolin-2-yl, alkoxy preferably methoxy, or fused to the heteroarylgroup may be one or more cycloalkyl, aryl, heterocyclyl or heteroarylmoiety, each of said substituents being optionally substituted by one ormore further substituent(s) selected from halo preferably bromo, chloroor fluoro, cyano, alkyl preferably methyl, haloalkyl preferably —CF₃ or—CHF₂, cyclopropyl, alkoxy preferably methoxy heterocyclyl optionallysubstituted by alkyl, preferably pyrrolidin-1yl, piperidin-1-yl,morpholin-4-yl, 4-methylpiperazin-1-yl, aryl preferably phenyl,hydroxyl, alkoxy preferably methoxy, alkoxyalkyl preferablymethoxymethyl, methoxyethyl, hydroxyalkoxy preferably hydroxyethoxy,alkylamino preferably dimethylamino, alkylsulfonylamino preferablymethylsulfonylamino, alkoxycarbonylamino preferablytert-butoxycarbonylamino, aminoalkoxy preferably aminoethyloxy, oralkoxycarbonylaminoalkoxy preferably tert-butoxycarbonylaminoethoxy,more preferably Ar² is a pyrazolyl, oxazolyl, thiazolyl, oxadiazolyltriazolyl, thiadiazolyl or pyridyl group, each of which being optionallysubstituted by one or more groups selected chloro, fluoro, cyano,methyl, isobutyl, C3-C6 cycloalkyl preferably cyclopropyl, heterocyclylpreferably pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, arylpreferably phenyl, heteroaryl preferably thiophen-2-yl, pyridin-2-yl,pyridin-4-yl, or fused to the oxazolyl, thiazolyl or pyridyl group maybe one cyclohexyl or phenyl moiety, each of said substituents beingoptionally substituted by one or more further substituent(s) selectedfrom bromo, chloro, fluoro, cyano, haloalkyl preferably —CF₃, methoxy,cyclopropyl, heterocyclyl optionally substituted by methyl, preferablypyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl,phenyl, hydroxyl, alkoxy preferably methoxy, alkoxyalkyl preferablymethoxyethyl, hydroxyalkoxy preferably hydroxyethoxy, alkylaminopreferably dimethylamino, alkylsulfonylamino preferablymethylsulfonylamino, aminoalkoxy preferably aminoethyloxy, even morepreferably Ar² is a pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl,thiadiazolyl or pyridyl group, each of which being optionallysubstituted by one or more groups selected chloro, fluoro, cyano,methyl, isobutyl, heterocyclyl preferably pyrrolidin-1-yl,piperidin-1-yl, morpholin-4-yl, 4-phenylpiperazin-1-yl, aryl preferablyphenyl, heteroaryl preferably thiophen-2-yl, pyridin-2-yl, or fused tothe oxazolyl, thiazolyl or pyridyl group may be one cyclohexyl or phenylmoiety, each of said substituents being optionally substituted by one ormore further substituent(s) selected from chloro, fluoro, cyano, methyl,cyclopropyl, phenyl, hydroxyl, alkoxy preferably methoxy, ormethoxyethyl.

Preferred compounds of formula Ib are those of formula Ic:

and pharmaceutically acceptable salts and solvates thereof, wherein adepicts the bond linking R¹ to the piperazine moiety, and Ar¹, Ar², R¹,R^(1′), X¹, and X² are as defined above in respect to formula Ib.

In one embodiment, compounds of formula Ic are those wherein R^(1′) isH, and/or X¹ and X² are N.

In another embodiment, compounds of formula Ic are those wherein bond ais drawn as a dotted wedge, R¹ is selected from the group consisting ofC₁-C₄ alkyl, aryl or aralkyl group, each of said alkyl, aryl or aralkylgroups being optionally substituted by one or more group(s) selectedfrom halo or hydroxyl, R^(1′) is H, and/or X¹ and X² are N.

In yet another embodiment, compounds of formula Ic are those whereinbond a is drawn as a solid wedge, R¹ is selected from the groupconsisting of C₁-C₄ alkyl, aryl or aralkyl group, each of said alkyl,aryl or aralkyl groups being optionally substituted by one or moregroup(s) selected from halo or hydroxyl, R^(1′) is H, and/or X¹ and X²are N.

Preferred compounds of formula Ic are those of formulae Id-1, Id-2, Id-3and Id-4:

and pharmaceutically acceptable salts and solvates thereof, whereina depicts the bond linking R¹ to the piperazine moiety; andAr², R¹, X¹ and X² are as defined above in respect to formula Ib; andR⁴, R^(4′), R⁵, R^(5′) and R⁶ are independently selected from H, halo,cyano, alkyl, haloalkyl, C3-C6 cycloalkyl, heteroalkyl, heterocyclyl,aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, alkoxyalkoxy,alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl,carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino,or R⁵ together with R⁴ or R⁶, or R^(5′) together with R^(4′) or R⁶ formsan alkylenedioxy group or a haloalkylenedioxy group, or R⁵ together withR⁴ or R⁶, or R^(5′) together with R^(4′) or R⁶ forms an aryl moietyfused to the phenyl group to which they are attached, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,preferably R⁴ and R^(4′) are H and at least one of R⁵, R^(5′), R⁶ isindependently selected from halo preferably chloro or fluoro, cyano,alkyl preferably methyl, haloalkyl preferably —CF₃ or —CHF₂, morepreferably —CF₃, cyclopropyl, aryl preferably phenyl, heteroarylpreferably thiophen-2-yl, thiophen-3-yl, or furan-2-yl, the others, ifapplicable, being H, each of said aryl and heteroaryl group beingoptionally substituted by one or more further substituent(s) selectedfrom halo preferably chloro or fluoro, alkyl preferably methyl,cyclopropyl, or R⁵ together with R⁴ or R⁶, or R^(5′) together withR^(4′) or R⁶ forms a phenyl moiety fused to the phenyl group to whichthey are attached, more preferably R⁴, R^(4′), R⁵, and R^(5′) are H andR⁶ is selected from cyano, phenyl, thiophen-2-yl, thiophen-3-yl, orfuran-2-yl, each of said group being optionally substituted by one ormore further substituent(s) selected from chloro, fluoro or methyl, orR⁴, R^(4′), R⁵ are H and R^(5′), R⁶ are independently selected fromfluoro or chloro, or R⁴ and R^(4′) are H and R⁵, R^(5′), R⁶ are fluoro;andR⁷ is H or methyl, preferably R⁷ is H; andR^(7′) is H or methyl, preferably R^(7′) is H; andAr⁴ is a cycloalkyl preferably cyclohexyl or an aryl preferably phenylgroup, each of said cycloalkyl or aryl groups being optionallysubstituted by one or more group(s) selected from halo preferably chloroor fluoro, alkyl preferably methyl, haloalkyl preferably —CF₃ or —CHF₂,more preferably —CF₃, cyclopropyl, haloalkoxy preferably —OCF₃ or—OCHF₂, more preferably —OCF₃, aryloxy preferably phenoxy; andM¹ is N or C—R^(4″) wherein R^(4″) is selected from H, halo, cyano,alkyl, haloalkyl, C3-C6 cycloalkyl, heteroalkyl, heterocyclyl, aryl,heteroaryl, hydroxyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino,carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl, carbamoylamino,alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,preferably R^(4″) is H; andM² is N or M² is C—R^(5″) under the condition that M¹ is N, whereinR^(5″) is selected from H, halo, cyano, alkyl, haloalkyl, C3-C6cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl,alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, carboxy, alkoxycarbonyl,alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl,alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,haloalkylsulfonylamino, or R^(5″) together with R⁶ forms analkylenedioxy group or a haloalkylenedioxy group, or an aryl moietyfused to the pyridinyl group to which they are attached, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,preferably R^(5″) is selected from H, halo preferably chloro or fluoro,alkyl preferably methyl, haloalkyl preferably —CF₃ or —CHF₂, morepreferably —CF₃, more preferably R^(5″) is H; andwherein, in formula Id-1 when:

R¹ is H, and X² is N, and

R⁴, R^(4′), R⁵, R^(5′) and R⁶ are independently selected from H, halo,cyano, C1-C3 alkyl, C1 haloalkyl, andAr² is a 5- to 6-membered aryl or heteroaryl group optionallysubstituted by one or more group(s) selected from halo, C1-C3 alkyl,hydroxyl, alkoxy, or fused to an aryl group optionally substituted byone or more further halo, C1-C3 alkyl, hydroxyl, methoxy,then,R⁴, R^(4′), R⁵, R^(5′) and R⁶ are H, or R⁴, R^(4′), R^(5′), R⁶ are H andR⁵ is halo, or R⁴, R^(4′), R⁵, R^(5′) are H and R⁶ is halo, cyano, C1-C3alkyl, C1 haloalkyl, or R^(4′), R^(5′), R⁶ are H and R⁴, R⁵ are halo, orR⁴, R^(4′), R^(5′) are H and R⁵, R⁶ are independently halo, or R⁴,R^(4′) are H and R⁵, R^(5′), R⁶ are halo, preferably, R⁴, R^(4′), R⁵,R^(5′) and R⁶ are H, or R⁴, R^(4′), R^(5′), R⁶ are H and R⁵ is fluoro,chloro, or R⁴, R^(4′), R⁵, R^(5′) are H and R⁶ is fluoro, chloro, cyano,methyl, trifluoromethyl, or R⁴, R^(4′), R^(5′) are H and R⁵, R⁶ areindependently fluoro, chloro, or R⁴, R^(4′) are H and R⁵, R^(5′), R⁶ arefluoro, andAr² is 2-(C1-C3 alkyl)thiazol-4-yl, 5-(C1-C3 alkyl)thiazol-4-yl,pyridin-2-yl, 4-halopyridin-2-yl, 4-(C1-C3 alkyl)pyridin-2-yl, 5-(C1-C3alkyl)pyridin-2-yl, 6-(C1-C3 alkyl)pyridin-2-yl, quinolin-2-yl,isoquinolin-3-yl, 8-haloquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, preferably Ar² is2-isopropylthiazol-4-yl, 5-methylthiazol-4-yl pyridin-2-yl,6-methylpyridin-2-yl, 5-methylpyridin-2-yl, 4-methylpyridin-2-yl,4-chloropyridin-2-yl, quinolin-2-yl, isoquinolin-3-yl,8-fluoroquinolin-2-yl, 8-chloroquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl.

In one embodiment, compounds of formulae Id-1, Id-2, Id-3 and Id-4 arethose wherein X¹ and X² are N.

In another embodiment, compounds of formulae Id-1, Id-2, Id-3 and Id-4are those wherein bond a is drawn as a dotted wedge, R¹ is selected fromthe group consisting of C₁-C₄ alkyl, aryl or aralkyl group, each of saidalkyl, aryl or aralkyl groups being optionally substituted by one ormore group(s) selected from halo or hydroxyl, and/or X¹ and X² are N.

In yet another embodiment, compounds of formulae Id-1, Id-2, Id-3 andId-4 are those wherein bond a is drawn as a solid wedge, R¹ is selectedfrom the group consisting of C₁-C₄ alkyl, aryl or aralkyl group, each ofsaid alkyl, aryl or aralkyl groups being optionally substituted by oneor more group(s) selected from halo or hydroxyl, and/or X¹ and X² are N.

Preferred compounds of formulae Id-1, Id-2, Id-3 and Id-4 are those offormulae Ie-1, Ie-2 and Ie-3:

and pharmaceutically acceptable salts and solvates thereof, whereina depicts the bond linking R¹ to the piperazine moiety; andAr², R¹, X¹ and X² are as defined above in respect to formula Ib; andR⁵ and R⁶ are independently selected from H, halo preferably chloro orfluoro, cyano, alkyl preferably methyl, cyclopropyl, aryl preferablyphenyl, heteroaryl, preferably thiophen-2-yl, thiophen-2-yl, furan-2-yl,each of said aryl and heteroaryl groups being optionally substituted byone or more group(s) selected from halo, preferably chloro or fluoro,alkyl preferably methyl, cyclopropyl, or R⁵ and R⁶ together form aphenyl moiety fused to the phenyl ring they are attached to, preferablyR⁵ is H and R⁶ is selected from H, chloro, fluoro, cyano, methyl,cyclopropyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl,4-tolyl, 3-tolyl, 2-tolyl, 2-fluorophenyl, 3,4-difluorophenyl,3,4-dichlorophenyl, 3-fluoro-4-chlorophenyl, 3,5-difluorophenyl,thiophen-2-yl, 5-methylthiophen-2-yl, 2-methylthiophen-3-yl, furan-2-yl,or R⁶ is H and R⁵ is selected from chloro, fluoro, methyl, cyclopropylor phenyl, or R⁵ and R⁶ are both chloro, more preferably R⁵ is H and R⁶is selected from H, chloro, fluoro, phenyl, 4-fluorophenyl,4-chlorophenyl, 4-cyanophenyl, 4-tolyl, 2-fluorophenyl,3,4-difluorophenyl, thiophen-2-yl, 5-methylthiophen-2-yl,2-methylthiophen-3-yl, or R⁶ is H and R⁵ is selected from chloro,fluoro, methyl or phenyl, or R⁵ and R⁶ are both chloro, even morepreferably R⁵ is H and R⁶ is selected from phenyl, 4-fluorophenyl,thiophen-2-yl, 5-methylthiophen-2-yl, 2-methylthiophen-3-yl, or R⁵ andR⁶ are both chloro; andR⁸, R^(8′), R⁹, R^(9′) and R¹⁰ are independently selected from H, halopreferably fluoro or chloro, haloalkyl preferably —CF₃ or —CHF₂, morepreferably —CF₃, cyclopropyl or haloalkoxy preferably —OCF₃ or —OCHF₂more preferably —OCF₃, or R⁸, R^(8′), R⁹, R^(9′) are H and R¹⁰ isphenoxy, preferably R^(8′), R⁹, R^(9′), R¹⁰ are H and R⁸ is —CF₃, or R⁸,R^(8′), R^(9′), R¹⁰ are H and R⁹ is selected from chloro or fluoro, orR⁸, R^(8′), R⁹, R^(9′) are H and R¹⁰ is selected from chloro, fluoro,—CF₃, —OCF₃ or —OCHF₂, phenoxy, or R⁸, R⁹, R^(9′) are H, R^(8′) isselected from chloro, fluoro —CF₃, and R¹⁰ is selected from fluoro orchloro, or R⁸, R^(8′), R^(9′) are H and R⁹, R¹⁰ are independentlyselected from fluoro or chloro, more preferably R⁸, R^(8′), R⁹, R^(9′)are H and R¹⁰ is selected from chloro, fluoro or phenoxy, or R⁸, R⁹,R^(9′) are H and R^(8′), R¹⁰ are both chloro, or R⁸, R^(8′), R^(9′) areH and R⁹, R¹⁰ are both chloro; andM¹ and M² are as defined above in respect to formula Id-4; andwherein, in formula Ie-1 when:

R¹ is H, and X² is N, and

R⁵ and R⁶ are independently selected from H, halo, cyano, C1-C3 alkyl,andAr² is a 5- to 6-membered aryl or heteroaryl group optionallysubstituted by one or more group(s) selected from halo, C1-C3 alkyl,hydroxyl, alkoxy, or fused to an aryl group optionally substituted byone or more further halo, C1-C3 alkyl, hydroxyl, methoxy,then,R⁶ is H and R⁵ is H, halo, or R⁵ is H and R⁶ is halo, cyano, C1-C3alkyl, C1 haloalkyl, or R⁵ andR⁶ are independently halo, preferably R⁶ is H and R⁵ is fluoro, chloro,or R⁵ is H and R⁶ is fluoro, chloro, cyano, methyl, trifluoromethyl orR⁵ and R⁶ are independently fluoro, chloro, andAr² is 2-(C1-C3 alkyl)thiazol-4-yl, 5-(C1-C3 alkyl)thiazol-4-yl,pyridin-2-yl, 4-halopyridin-2-yl, 4-(C1-C3 alkyl)pyridin-2-yl, 5-(C1-C3alkyl)pyridin-2-yl, 6-(C1-C3 alkyl)pyridin-2-yl, quinolin-2-yl,isoquinolin-3-yl, 8-haloquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl, preferably Ar² is2-isopropylthiazol-4-yl, 5-methylthiazol-4-yl, pyridin-2-yl,6-methylpyridin-2-yl, 5-methylpyridin-2-yl, 4-methylpyridin-2-yl,4-chloropyridin-2-yl, quinolin-2-yl, isoquinolin-3-yl,8-fluoroquinolin-2-yl, 8-chloroquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl.

In one embodiment, compounds of formulae Ie-1, Ie-2 and Ie-3 are thosewherein X¹ and X² are N.

In another embodiment, compounds of formulae Ie-1, Ie-2 and Ie-3 arethose wherein bond a is drawn as a dotted wedge, R¹ is selected from thegroup consisting of C₁-C₄ alkyl, aryl or aralkyl group, each of saidalkyl, aryl or aralkyl groups being optionally substituted by one ormore group(s) selected from halo or hydroxyl, and/or X¹ and X² are N.

In yet another embodiment, compounds of formulae Ie-1, Ie-2 and Ie-3 arethose wherein bond a is drawn as a solid wedge, R¹ is selected from thegroup consisting of C₁-C₄ alkyl, aryl or aralkyl group, each of saidalkyl, aryl or aralkyl groups being optionally substituted by one ormore group(s) selected from halo or hydroxyl, and/or X¹ and X² are N.

Other preferred compounds of formula Ic are those of formulae If-1,If-2, If-3, If-4, If-5, If-6, If-7 and If-8:

and pharmaceutically acceptable salts and solvates thereof, whereina designates the bond linking R¹ to the piperazine moiety; andAr¹, R¹, X¹ and X² are as defined above in respect to formula Ib; andR¹¹, R¹², R^(12′) and R¹³ are independently selected from H, halo,cyano, alkyl, hydroxyalkyl, haloalkyl, C3-C6 cycloalkyl, heteroalkyl,heterocyclyl, aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy,alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, acylamino, carbamoyl,alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl,alkylsulfonylamino, haloalkylsulfonylamino, or R¹² together with R¹¹ orR¹³, or R¹³ together with R^(12′) forms an alkylenedioxy group or ahaloalkylenedioxy group, or R¹² together with R¹¹ or R¹³ forms acycloalkyl, aryl, heterocyclyl or heteroaryl moiety fused to the pyridylgroup to which they are attached, each of said groups being optionallysubstituted by one or more group(s) selected from halo, cyano, alkyl,haloalkyl, cyclopropyl, alkoxy, haloalkoxy or hydroxyl, preferably R¹¹,R¹², R^(12′) and R¹³ are independently selected from H, halo preferablychloro or fluoro, alkyl preferably methyl, haloalkyl preferably —CF₃ or—CHF₂, more preferably —CF₃, C3-C6 cycloalkyl, preferably cyclopropyl,heterocyclyl preferably pyrrolidin-1-yl, morpholin-4-yl, aryl preferablyphenyl, or R¹² together with R¹¹ or R¹³ forms an aryl preferably phenylmoiety fused to the pyridyl group to which they are attached, each ofsaid groups being optionally substituted by one or more group(s)selected from halo, cyano, alkyl, haloalkyl, alkoxy or haloalkoxy morepreferably R¹², R^(12′) and R¹³ are H and R¹¹ is selected from methyl,—CF₃, cyclopropyl, pyrrolidin-1-yl, morpholin-4-yl or phenyl, or R¹¹,R^(12′), R¹³ are H and R¹² is methyl, cyclopropyl, or R¹¹, R¹², R^(12′)are H and R¹³ is selected from chloro or methyl, cyclopropyl, or R¹²together with R¹¹ or R¹³ forms an aryl preferably phenyl moiety fused tothe pyridyl group to which they are attached, thus forming a fused ringsystem, each of said phenyl and fused ring system being optionallysubstituted by one or more halo preferably chloro or fluoro, still morepreferably R¹², R^(12′) and R¹³ are H and R¹¹ is selected from methyl,pyrrolidin-1-yl or morpholin-4-yl, or R¹² together with R¹¹ forms aphenyl moiety fused to the pyridyl group to which they are attached,thus forming a quinoline moiety, each of said phenyl and quinolinegroups being optionally substituted by one or more group(s) selectedfrom halo preferably chloro or fluoro, even more preferably R¹², R^(12′)and R¹³ are H and R¹¹ is methyl, or R¹² together with R¹¹ forms a phenylmoiety fused to the pyridyl group to which they are attached, thusforming a quinoline moiety; andAr⁵ is a heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, orarylsulfonylalkyl group, each of which being optionally substituted byone or more group(s) selected from halo, cyano, alkyl, haloalkyl,cyclopropyl, alkoxy, haloalkoxy, heterocyclyl optionally substituted byalkyl, aryl, hydroxyl, alkoxy, alkoxyalkyl, hydroxyalkoxy, alkylamino,alkylsulfonylamino, aminoalkoxy, or alkoxycarbonylaminoalkoxy preferablytert-butyloxycarbonylaminoethoxy, preferably Ar⁵ is pyrrolidin-1-yl,morpholin-4-yl, piperidin-1-yl, 4-methylpiperazin-1-yl, each of whichbeing optionally substituted by one or more halo preferably fluoro,alkyl preferably methyl, alkoxyalkyl preferably methoxymethyl,methoxyethyl, or Ar⁵ is 4-phenyl-piperazin-1-yl or a phenyl groupoptionally substituted by one or more group(s) selected from halopreferably bromo, chloro or fluoro, cyano, haloalkyl preferably —CF₃ or—CHF₂, more preferably —CF₃, cyclopropyl, hydroxyl, alkoxy preferablymethoxy, heterocyclyl optionally substituted by alkyl, preferablypyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl,hydroxyalkoxy preferably hydroxyethoxy, alkylamino preferablydimethylamino, alkylsulfonylamino preferably methylsulfonylamino,aminoalkoxy preferably aminoethoxy, or Ar⁵ is thiophen-2-yl,pyridin-2-yl, pyridin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, quinolin-2-yl,4-chlorobenzyl, 4,5-dichloro(imidazol-3-yl)methyl,4-chlorophenylsulfonylmethyl more preferably Ar⁵ is a phenyl optionallysubstituted by one or more group(s) selected from chloro or fluoro,cyano, —CF₃, hydroxyl, methoxy, 4-methylpiperazin-1-yl hydroxyethoxy orAr⁵ is thiophen-2-yl, pyridin-2-yl even more preferably Ar⁵ is phenyl,2-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-fluorophenyl,3-chlorophenyl, 2-chlorophenyl, 2,4-difluorophenyl or2,4-dichlorophenyl, 4-cyanophenyl; andX³ is O or S, preferably X³ is S; andR¹⁴ is H or methyl, preferably R¹⁴ is H; andAr⁶ is a heterocyclyl, aryl or heteroaryl group, each of which beingoptionally substituted by one or more group(s) selected from halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy, aryl orhydroxyl, preferably Ar⁶ is a phenyl group optionally substituted by oneor more group(s) selected from halo preferably chloro or fluoro,haloalkyl preferably —CF₃ or —CHF₂, cyclopropyl, more preferably —CF₃,or alkoxy preferably methoxy, more preferably Ar⁶ is phenyl,4-fluorophenyl, 2,4-difluorophenyl; andR¹⁵ is H or methyl, preferably R¹⁵ is methyl; andR¹⁶ is a heterocyclyl, aryl or heteroaryl group, each of said groupsbeing optionally substituted by one or more group(s) selected from halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy or hydroxyl,preferably R¹⁶ is a phenyl group optionally substituted by one or moregroup(s) selected from halo preferably chloro or fluoro, haloalkylpreferably —CF₃ or —CHF₂, more preferably —CF₃, alkoxy preferablymethoxy, more preferably R¹⁶ is phenyl; andR¹⁷ is H, methyl or R¹⁷ together with R¹⁶ forms a cycloalkyl or arylmoiety fused to the thiazolyl group to which they are attached, thusforming a fused ring system, said fused ring system being optionallysubstituted by one or more group(s) selected from halo, cyano, alkyl,haloalkyl, cyclopropyl, alkoxy, haloalkoxy or hydroxyl, preferably R¹⁷is H or R¹⁷ together with R¹⁶ forms a cyclohexyl or phenyl moiety fusedto the thiazolyl group to which they are attached, more preferably R¹⁷together with R¹⁶ forms a cyclohexyl or phenyl moiety fused to thethiazolyl group to which they are attached; andX⁵ is O or S, or N—R³⁶ wherein R³⁶ is H or C1-C3 alkyl, preferably X⁵ isO or S, more preferably X⁵ is O; andAr⁷ is a heterocyclyl, aryl or heteroaryl group, each of which beingoptionally substituted by one or more group(s) selected from halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy, aryl orhydroxyl, preferably Ar⁷ is a phenyl group optionally substituted by oneor more group(s) selected from halo preferably chloro or fluoro,haloalkyl preferably —CF₃ or —CHF₂, more preferably —CF₃, or alkoxypreferably methoxy, more preferably Ar⁷ is phenyl, 4-fluorophenyl,2,4-difluorophenyl; andX⁶ is O, S or N—R^(36′) wherein R^(36′) is H or C1-C3 alkyl, preferablyX⁶ is O or NH, more preferably X⁶ is O; andR^(14′) is H or methyl, preferably R^(14′) is H; andR³⁴ is H, alkyl, alkoxyalkyl, hydroxyalkyl, alkoxycarbonylaminoalkyl,preferably R³⁴ is H, methyl, ethyl, hydroxyethyl, methoxyethyl,tert-butoxycarbonylaminoethyl, more preferably R³⁴ is H, methyl,hydroxyethyl, methoxyethyl; andR³⁵ is H, alkyl, alkoxyalkyl, hydroxyalkyl, alkoxycarbonylaminoalkyl,preferably R³⁵ is H, methyl, ethyl, hydroxyethyl, methoxyethyl,tert-butoxycarbonylaminoethyl, more preferably R³⁵ is H, methyl,hydroxyethyl; and wherein,

-   -   in formula If-1 when:        -   R¹ is H, and        -   X² is N, and        -   Ar¹ is a 6-membered aryl optionally substituted by one or            more group(s) selected from halo, cyano, C1-C3 alkyl,            C1-haloalkyl, and        -   R¹¹, R¹², R^(12′) and R¹³ are independently selected from H,            halo, C1-C3 alkyl, hydroxyl, methoxy, or R¹² together with            R¹ or R¹³ forms an aryl or heterocyclyl or heteroaryl moiety            fused to the pyridyl group to which they are attached and            being optionally substituted by one or more group(s)            selected from halo, C1-C3 alkyl, methoxy or hydroxyl,        -   then,        -   Ar¹ is phenyl, 3-halophenyl, 4-halophenyl,            2,3-dichlorophenyl, 3,4-dihalophenyl, 3,4,5-trihalophenyl,            4-cyanophenyl, 4-(C1-C3 alkyl)phenyl, 4-(C1            haloalkyl)phenyl, preferably Ar¹ is phenyl, 4-fluorophenyl,            4-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl,            3,4-dichlorophenyl, 3,4-difluorophenyl,            3,4,5-trifluorophenyl, 4-chloro-3-fluorophenyl,            3-chloro-4-fluorophenyl, 4-cyanophenyl, 4-tolyl,            4-trifluoromethylphenyl, and        -   R¹¹, R¹², R^(12′) and R¹³ are H, or R¹¹, R¹², R^(12′) are H            and R¹³ is halo, C1-C3 alkyl, or R¹¹, R^(12′), R¹³ are H and            R¹² is C1-C3 alkyl, or R¹², R^(12′), R¹³ are H and R¹¹ is            C1-C3 alkyl, or R¹¹, R¹², R^(12′) and R¹³ together with the            pyridyl group they are attached form a quinolin-2-yl,            isoquinolin-3-yl or 8-haloquinolin-2-yl moiety, preferably            R¹¹, R¹², R^(12′) and R¹³ are H, or R¹¹, R¹², R^(12′) are H            and R¹³ is chloro, methyl, or R¹¹, R^(12′), R¹³ are H and            R¹² is methyl, or R¹², R^(12′), R¹³ are H and R¹¹ is methyl,            or R¹¹, R¹², R^(12′) and R¹³ together with the pyridyl group            they are attached form a quinolin-2-yl, isoquinolin-3-yl,            8-fluoroquinolin-2-yl or 8-chloroquinolin-2-yl moiety; and    -   in formula If-4 when:        -   R¹ is H, and        -   X² is N, and        -   Ar¹ is a 6-membered aryl optionally substituted by one or            more group(s) selected from halo, cyano, C1-C3 alkyl,            C1-haloalkyl, and        -   R¹⁷ together with R¹⁶ forms a cycloalkyl or aryl moiety            fused to the thiazolyl group to which they are attached,            thus forming a fused ring system, said fused ring system            being optionally substituted by one or more group(s)            selected from halo, C1-3 alkyl, methoxy or hydroxyl,        -   then        -   Ar¹ is phenyl, 3-halophenyl, 4-halophenyl,            2,3-dichlorophenyl, 3,4-dihalophenyl, 3,4,5-trihalophenyl,            4-cyanophenyl, 4-(C1-C3 alkyl)phenyl, 4-(C1            haloalkyl)phenyl, preferably Ar¹ is phenyl, 4-fluorophenyl,            4-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl,            3,4-dichlorophenyl, 3,4-difluorophenyl,            3,4,5-trifluorophenyl, 4-chloro-3-fluorophenyl,            3-chloro-4-fluorophenyl, 4-cyanophenyl, 4-tolyl,            4-trifluoromethylphenyl, and        -   R¹⁷ and R¹⁶ form together with the thiazolyl group to which            they are attached a benzothiazol-2-yl or            4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl moiety.

In one embodiment, compounds of formulae If-1, If-2, If-3, If-4, If-5,If-6, If-7 and If-8 are those wherein X¹ and X² are N.

In another embodiment, compounds of formulae If-1, If-2, If-3, If-4,If-5, If-6, If-7 and If-8 are those wherein bond a is drawn as a dottedwedge, R¹ is selected from the group consisting of C₁-C₄ alkyl, aryl oraralkyl group, each of said alkyl, aryl or aralkyl groups beingoptionally substituted by one or more group(s) selected from halo orhydroxyl, and/or X¹ and X² are N.

In yet another embodiment, compounds of formulae If-1, If-2, If-3, If-4,If-5, If-6, If-7 and If-8 are those wherein bond a is drawn as a solidwedge, R¹ is selected from the group consisting of C₁-C₄ alkyl, aryl oraralkyl group, each of said alkyl, aryl or aralkyl groups beingoptionally substituted by one or more group(s) selected from halo orhydroxyl, and/or X¹ and X² are N.

Preferred compounds of formulae If-1, If-2, If-3, If-4, If-5, If-6, If-7and If-8 are those of formulae Ig-1, Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7and Ig-8 respectively:

and pharmaceutically acceptable salts, and solvates thereof, whereina depicts the bond linking R¹ to the piperazine moiety; andAr¹, R¹, X¹ and X² are as defined above in respect to formula Ib; andR^(12′) and R¹³ are independently selected from H, halo, cyano, alkyl,hydroxyalkyl, haloalkyl, cycloalkyl, heteroalkyl, hydroxyl, alkoxy,haloalkoxy, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, acylamino, carbamoyl,alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl,alkylsulfonylamino, haloalkylsulfonylamino, or R¹³ together with R^(12′)forms an alkylenedioxy group or a haloalkylenedioxy group, each of saidgroups being optionally substituted by one or more group(s) selectedfrom halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl or oxo,preferably, R^(12′) and R¹³ are independently selected from H, halopreferably chloro or fluoro, alkyl preferably methyl, haloalkylpreferably —CF₃ or —CHF₂, more preferably —CF₃, more preferably R^(12′)and R¹³ are H; andX³ is as defined above in respect to formula If-2, preferably X³ is S;andR¹⁸, R¹⁹, R^(19′) and R²⁰ are independently selected from H, halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy, preferablyR¹⁹, R^(19′) and R²⁰ are H and R¹⁸ is selected from H, fluoro or chloro,more preferably R¹⁸, R¹⁹, R^(19′) and R²⁰ are H; andR¹⁴ is as defined above in respect to formula If-2; andR²¹, R^(21′), R²², R^(22′) and R²³ are independently selected from H,halo preferably bromo, chloro or fluoro, cyano, alkyl, haloalkylpreferably —CF₃ or —CHF₂, more preferably —CF₃, cyclopropyl,heterocyclyl optionally substituted by alkyl, preferablypyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl,hydroxyl, alkoxy preferably methoxy, haloalkoxy, hydroxyalkoxypreferably hydroxyethoxy, alkylamino preferably dimethylamino,alkylsulfonylamino preferably methylsulfonylamino, aminoalkoxypreferably aminoethoxy, alkoxycarbonylaminoalkoxy preferablytert-butyloxycarbonylaminoethoxy, preferably R²¹, R^(21′), R²² andR^(22′) are H and R²³ is selected from bromo, fluoro, chloro, cyano,methyl —CF₃, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl,4-methylpiperazin-1-yl methoxy, dimethylamino or methylsulfonylamino, orR²¹, R^(21′), R^(22′) and R²³ are H and R²² is selected from fluoro,chloro, bromo, cyano, —CF₃, dimethylamino or methylsulfonylamino orR^(21′), R²², R^(22′) and R²³ are H and R²¹ is fluoro, chloro, bromo,cyano, hydroxyl, methoxy, hydroxyethoxy, dimethylamino,methylsulfonylamino, aminoethoxy or tert-butoxycarbonylaminoethoxy orR^(21′), R²², R^(22′) are H and R²¹ and R²³ are independently selectedfrom H, chloro or fluoro, or R^(21′), R^(22′), and R²³ are H and R²¹ andR²² are chloro, or R²¹, R^(21′) and R²³ are H and R²² and R^(22′) arechloro, more preferably R²¹, R^(21′), R²² and R^(22′) are H and R²³ isselected from fluoro or chloro, cyano, or R²¹, R^(21′), R^(22′) and R²³are H and R²² is chloro, or R^(21′), R²², R^(22′) and R²³ are H and R²¹is chloro, or R^(21′), R²², R^(22′) are H and R²¹ and R²³ areindependently selected from H, chloro or fluoro, even more preferablyR²¹, R^(21′), R²² and R^(22′) are H and R²³ is selected from H, fluoro,chloro, cyano, or R^(21′), R²², R^(22′) are H and R²¹ and R²³ areindependently selected from H, chloro or fluoro; andR¹⁵ is as defined above in respect to formula If-3, preferably R¹⁵ ismethyl; andR²⁴, R^(24′), R²⁵, R^(25′) and R²⁶ are independently selected from H,halo preferably chloro or fluoro, haloalkyl preferably —CF₃ or —CHF₂,more preferably —CF₃, cyclopropyl, preferably R²⁴, R^(24′), R²⁵, R^(25′)are H and R²⁶ is selected from H, chloro or fluoro, more preferably R²⁴,R^(24′), R²⁵, R^(25′) and R²⁶ are H; andR²⁷, R²⁸, R²⁹ and R³⁰ are independently selected from H, halo, cyano,alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy, preferably R²⁸, R²⁹and R³⁰ are H and R²⁷ is selected from H, fluoro or chloro, morepreferably R²⁷, R²⁸, R²⁹ and R³⁰ are H; andR^(27′), R^(28′), R^(29′) and R^(30′) are absent, or R^(27′), R^(28′),R^(29′) and R^(30′) are H under the condition that R²⁸, R²⁹ and R³⁰ areH and that R²⁷ is selected from H, chloro or fluoro preferably R^(27′),R^(28′), R^(29′) and R^(30′) are absent or H under the condition thatR²⁷, R²⁸, R²⁹ and R³⁰ are H; andthe two bonds represented by the dotted lines in formula Ig-4 are bothabsent, or both present under the condition that R^(27′), R^(28′),R^(29′) and R^(30′) are absent; andX⁵ is as defined above in respect to formula If-5, preferably X⁵ is O;andR³¹, R^(31′), R³², R^(32′) and R³³ are independently selected from H,halo preferably chloro or fluoro, cyano, alkyl, haloalkyl preferably—CF₃ or —CHF₂, more preferably —CF₃, cyclopropyl, alkoxy preferablymethoxy, haloalkoxy, preferably R³¹, R^(31′), R³² and R^(32′) are H andR³³ is selected from fluoro, chloro, cyano, —CF₃ or methoxy, or R³¹,R^(31′), R^(32′) and R³³ are H and R³² is selected from chloro or —CF₃,or R^(31′), R³², R^(32′) and R³³ are H and R³¹ is chloro, or R^(31′),R³², R^(32′) are H and R³¹ and R³³ are independently selected from H,chloro or fluoro, or R^(31′), R^(32′), and R³³ are H and R³¹ and R³² arechloro, or R³¹, R^(31′) and R³³ are H and R³² and R^(32′) are chloro,more preferably R³¹, R^(31′), R³² and R^(32′) are H and R³³ is selectedfrom fluoro, chloro or cyano or R³¹, R^(31′), R^(32′) and R³³ are H andR³² is chloro, or R^(31′), R³², R^(32′) and R³³ are H and R³¹ is chloro,or R^(31′), R³², R^(32′) are H and R³¹ and R³³ are independentlyselected from H, chloro or fluoro, even more preferably R³¹, R^(31′),R³² and R^(32′) are H and R³³ is selected from H, fluoro or chloro, orR^(31′), R³², R^(32′) are H and R³¹ and R³³ are fluoro; andX⁶ is as defined above in respect to formula If-6; andR^(14′) is as defined above in respect to formulae If-7 and If-8,preferably R^(14′) is H; andR³⁴ and R³⁵ are as defined above in respect to formula If-7; andwherein,

-   -   in formula Ig-1 when:        -   R¹ is H, and        -   X² is N, and        -   Ar¹ is a 6-membered aryl optionally substituted by one or            more group(s) selected from halo, cyano, C1-C3 alkyl,            C1-haloalkyl, and        -   R^(12′), R¹³, R¹⁸, R¹⁹, R^(19′) and R²⁰ are independently            selected from H, halo, C1-3 alkyl, hydroxyl, methoxy,        -   then,        -   Ar¹ is phenyl, 3-halophenyl, 4-halophenyl,            2,3-dichlorophenyl, 3,4-dihalophenyl, 3,4,5-trihalophenyl,            4-cyanophenyl, 4-(C1-C3 alkyl)phenyl, 4-(C1            haloalkyl)phenyl, preferably Ar¹ is phenyl, 4-fluorophenyl,            4-chlorophenyl, 4-trifluoromethylphenyl, 3-chlorophenyl,            3-fluorophenyl, 3,4-dichlorophenyl, 3,4-difluorophenyl,            3,4,5-trifluorophenyl, 4-chloro-3-fluorophenyl,            3-chloro-4-fluorophenyl, 4-cyanophenyl, 4-tolyl,            4-trifluoromethylphenyl, and        -   R^(12′), R¹³, R¹⁸, R¹⁹, R^(19′) and R²⁰ are H, or R^(12′),            R¹³, R¹⁹, R^(19′), R²⁰ are H and R¹⁸ is fluoro, chloro, and    -   in formula Ig-4 when        -   R¹ is H, and        -   X² is N, and        -   Ar¹ is a 6-membered aryl optionally substituted by one or            more group(s) selected from halo, cyano, C1-C3 alkyl,            C1-haloalkyl, and        -   R²⁷, R²⁸, R²⁹ and R³⁰ are independently selected from H,            halo, C1-3 alkyl, methoxy, and        -   R^(27′), R^(28′), R^(29′) and R^(30′) are absent or H under            the condition that R²⁸, R²⁹ and R³⁰ are H and R²⁷ is            selected from H, chloro or fluoro,        -   then        -   Ar¹ is phenyl, 3-halophenyl, 4-halophenyl,            2,3-dichlorophenyl, 3,4-dihalophenyl, 3,4,5-trihalophenyl,            4-cyanophenyl, 4-(C1-C3 alkyl)phenyl, 4-(C1            haloalkyl)phenyl, preferably Ar¹ is phenyl, 4-fluorophenyl,            4-chlorophenyl, 3-chlorophenyl, 3-fluorophenyl,            3,4-dichlorophenyl, 3,4-difluorophenyl,            3,4,5-trifluorophenyl, 4-chloro-3-fluorophenyl,            3-chloro-4-fluorophenyl, 4-cyanophenyl, 4-tolyl,            4-trifluoromethylphenyl, and        -   R²⁷, R²⁸, R²⁹ and R³⁰ are H, and        -   R^(27′), R^(28′), R^(29′) and R^(30′) are absent or H under            the condition that R²⁷, R²⁸, R²⁹ and R³⁰ are H.

In one embodiment, compounds of formulae Ig-1, Ig-2, Ig-3, Ig-4, Ig-5,Ig-6, Ig-7 and Ig-8 are those wherein X¹ and X² are N.

In another embodiment, compounds of formulae Ig-1, Ig-2, Ig-3, Ig-4,Ig-5, Ig-6, Ig-7 and Ig-8 are those wherein bond a is drawn as a dottedwedge, R¹ is selected from the group consisting of C₁-C₄ alkyl, aryl oraralkyl group, each of said alkyl, aryl or aralkyl groups beingoptionally substituted by one or more group(s) selected from halo orhydroxyl, and/or X¹ and X² are N.

In yet another embodiment, compounds of formulae Ig-1, Ig-2, Ig-3, Ig-4,Ig-5, Ig-6, Ig-7 and Ig-8 are those wherein bond a is drawn as a solidwedge, R¹ is selected from the group consisting of C₁-C₄ alkyl, aryl oraralkyl group, each of said alkyl, aryl or aralkyl groups beingoptionally substituted by one or more group(s) selected from halo orhydroxyl, and/or X¹ and X² are N.

Other preferred compounds of formulae If-1 and If-2, are those offormulae Ih-1 and Ih-2 respectively:

and pharmaceutically acceptable salts and solvates thereof, whereina designates the bond linking R¹ to the piperazine moiety; andAr¹, R¹, X¹ and X² are as defined above in respect to formula Ib; andR¹², R^(12′) and R¹³ are as defined above in respect to formula If-1,preferably R¹², R^(12′) and R¹³ are H; andR^(14″) is H or methyl; andX³ is as defined above in respect to formula If-2, preferably X³ is S;andX⁴ is O, CH₂, CF₂, C(CH₃)₂, N—(C1-C3 alkyl)N-phenyl, preferably X⁴ is O,CH₂, CF₂, N-methyl or N-phenyl; andR^(36a), R^(36b), R^(36′a), R^(37a) and R^(37′a) are independentlyselected from H, C1-C3 alkyl, alkoxy C1-C3 alkyl, preferably R^(36a),R^(36b), R^(37a) and R^(37′a) are H and R^(36′a) is H, methyl,methoxyethyl, or R^(36a)R^(36b), R^(37′a) are H and R^(37a) and R^(36′a)are methyl, or R^(36b), R^(37a), R^(37′a) are H and R^(36a) and R^(36′)are methyl, or R^(36′a), R^(37a), R^(37′a) are H and R^(36a) and R^(36b)are methyl, or R^(36a), R^(36b), R^(36′a), R^(37a) are H and R^(37′a) ismethoxymethyl.

In one embodiment, compounds of formula Ih-1 are those wherein X¹ and X²are N.

In another embodiment, compounds of formula Ih-1 are those wherein bonda is drawn as a dotted wedge and/or X¹ and X² are N.

In another embodiment, compounds of formula Ih-1 are those wherein bonda is drawn as a solid wedge and/or X¹ and X² are N.

In another embodiment, compounds of formula Ih-2 are those wherein X¹and X² are N.

In another embodiment, compounds of formula Ih-2 are those wherein bonda is drawn as a dotted wedge and/or X¹ and X² are N. In one variant ofthis embodiment, compounds of formula Ih-2 are those wherein bond a isdrawn as a dotted wedge, X¹ and X² are N and R^(36a), R^(36b),R^(36′a)R^(37a) and R^(37′a) are H.

In yet another embodiment, compounds of formula Ih-2 are those whereinbond a is drawn as a solid wedge and/or X¹ and X² are N. In one variantof this embodiment, compounds of formula Ih-2 are those wherein bond ais drawn as a solid wedge, X¹ and X² are N and R^(36a), R^(36b),R^(36′a), R^(37a) and R^(37′a) are H.

Other preferred compounds of formula Ic are those of formulae Ii-1,Ii-2, Ii-3, Ii-4, Ii-5, Ii-6, Ii-7, Ii-8, Ij-1, Ij-2, Ij-3, Ij-4, Ij-5,Ij-6, Ij-7, Ij-8, Ik-1, Ik-2, Ik-3, Ik-4 Ik-5, Ik-6, Ik-7, Ik-8, Ii′-1,Ii′-2, Ii′-3, Ii′-4, Ii′-5, Ii′-6, Ii′-7 and Ii′-8,

and pharmaceutically acceptable salts and solvates thereof, whereina depicts the bond linking R¹ to the piperazine moiety; andR¹, X¹ and X² are as defined above in respect to formula Ib; andR⁴, R^(4′), R⁵, R^(5′) and R⁶ are as defined above in respect to formulaId-1; andAr⁴, R⁷ and R^(7′) are as defined above in respect to formulae Id-2 andId-3; andM¹ and M² are as defined above in respect to formula Id-4; andR¹¹, R¹², R^(12′) and R¹³ are as defined above in respect to formulaIf-1; andAr⁵, R¹⁴ and X³ are as defined above in respect to formula If-2; andAr⁶ and R¹⁵ are as defined above in respect to formula If-3; andR¹⁶ and R¹⁷ are as defined above in respect to formula If-4: andAr⁷ and X⁵ are as defined above in respect to formula If-5; andX⁶ is as defined above in respect to formula If-6; andR^(14′), R³⁴ and R³⁵ are as defined above in respect to formulae If-7and If-8.

Among the compounds of formulae Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6,Ii-7, Ii-8, Ij-1, Ij-2, Ij-3, Ij-4, Ij-5, Ij-6, Ij-7, Ij-8, Ik-1, Ik-2,Ik-3, Ik-4 Ik-5, Ik-6, Ik-7, Ik-8, Ii′-1, Ii′-2, Ii′-3, Ii′-4, Ii′-5,Ii′-6, Ii′-7 and Ii′-8, compounds of formulae Ii-1, Ii-2, Ii-3, Ii-4,Ii-5, Ii-6, Ii-7, Ii-8, Ii′-1, Ii′-2, Ii′-3, Ii′-4, Ii′-5, Ii′-6, Ii′-7and Ii′-8 are preferred.

In one embodiment, compounds of Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6,Ii-7, Ii-8, Ij-1, Ij-2, Ij-3, Ij-4, Ij-5, Ij-6, Ij-7, Ij-8, Ik-1, Ik-2,Ik-3, Ik-4 Ik-5, Ik-6, Ik-7, Ik-8, Ii′-1, Ii′-2, Ii′-3, Ii′-4, Ii′-5,Ii′-6, Ii′-7 and Ii′-8 are those wherein X¹ and X² are N.

In another embodiment, compounds of formulae Ii-1, Ii-2, Ii-3, Ii-4,Ii-5, Ii-6, Ii-7, Ii-8, Ij-1, Ij-2, Ij-3, Ij-4, Ij-5, Ij-6, Ij-7, Ij-8,Ik-1, Ik-2, Ik-3, Ik-4 Ik-5, Ik-6, Ik-7, Ik-8, Ii′-1, Ii′-2, Ii′-3,Ii′-4, Ii′-5, Ii-6, Ii-7 and Ii-8 are those wherein bond a is drawn as adotted wedge, R¹ is selected from the group consisting of C₁-C₄ alkyl,aryl or aralkyl group, each of said alkyl, aryl or aralkyl groups beingoptionally substituted by one or more group(s) selected from halo orhydroxyl, and/or X¹ and X² are N.

In yet another embodiment, compounds of formulae Ii-1, Ii-2, Ii-3, Ii-4,Ii-5, Ii-6, Ii-7, Ii-8, Ij-1, Ij-2, Ij-3, Ij-4, Ij-5, Ij-6, Ij-7, Ij-8,Ik-1, Ik-2, Ik-3, Ik-4 Ik-5, Ik-6, Ik-7, Ik-8, Ii′-1, Ii′-2, Ii′-3,Ii′-4, Ii′-5, Ii-6, Ii-7 and Ii-8 are those wherein bond a is drawn as asolid wedge, R¹ is selected from the group consisting of C₁-C₄ alkyl,aryl or aralkyl group, each of said alkyl, aryl or aralkyl groups beingoptionally substituted by one or more group(s) selected from halo orhydroxyl, and/or X¹ and X² are N.

Preferred compounds of formulae Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6,Ii-7, Ii-8, Ii′-1, Ii′-2, Ii′-3, Ii′-4, Ii′-5, Ii′-6, Ii′-7 and Ii′-8are those of formulae Il-1, Il-2, Il-3, Il-4, Il-5, Il-6, Il-7, Il-8,Il′-1, Il′-2, Il′-3, Il′-4, Il′-5, Il′-6, Il′-7 and Il′-8 respectively:

and pharmaceutically acceptable salts and solvates thereof, wherein:a depicts the bond linking R¹ to the piperazine moiety; andR¹, X¹ and X² are as defined above in respect to formula Ib; andR⁴, R^(4′), R⁵, R^(5′) and R⁶ are as defined above in respect to formulaId-1; andM¹ and M² are as defined above in respect to formula Id-4; andR^(12′), R¹³, R¹⁴, R^(14′), R¹⁵, R¹⁸, R¹⁹, R^(19′), R²⁰, R²¹, R^(21′),R²², R^(22′), R²³, R²⁴, R^(24′), R²⁵, R^(25′), R²⁶, R²⁷, R^(27′), R²⁸,R^(28′), R²⁹, R^(29′), R³⁰, R^(30′), R³¹, R^(31′), R³², R^(32′), R³³,R³⁴, R³⁵, X³, X⁵, X⁶; and the two bonds represented by the dotted linesare as defined above in respect of formulae Ig-1, Ig-2, Ig-3, Ig-4,Ig-5, Ig-6, Ig-7 and Ig-8.

In one embodiment, compounds of formulae Il-1, Il-2, Il-3, Il-4, Il-5,Il-6, Il-7, Il-8, Il′-1, Il′-2, Il′-3, Il′-4, Il′-5, Il′-6, Il′-7 andIl′-8 are those wherein X¹ and X² are N.

In another embodiment, compounds of formulae Il-1, Il-2, Il-3, Il-4,Il-5, Il-6, Il-7, Il-8, Il′-1, Il′-2, Il′-3, Il′-4, Il′-5, Il′-6, Il′-7and Il′-8 are those wherein bond a is drawn as a dotted wedge, R¹ isselected from the group consisting of C₁-C₄ alkyl, aryl or aralkylgroup, each of said alkyl, aryl or aralkyl groups being optionallysubstituted by one or more group(s) selected from halo or hydroxyl,and/or X¹ and X² are N.

In yet another embodiment, compounds of formulae Il-1, Il-2, Il-3, Il-4,Il-5, Il-6, Il-7, Il-8, Il′-1, Il′-2, Il′-3, Il′-4, Il′-5, Il′-6, Il′-7and Il′-8 are those wherein bond a is drawn as a solid wedge, R¹ isselected from the group consisting of C₁-C₄ alkyl, aryl or aralkylgroup, each of said alkyl, aryl or aralkyl groups being optionallysubstituted by one or more group(s) selected from halo or hydroxyl,and/or X¹ and X² are N.

Preferred compounds of formulae Il-1, Il-2, Il-3, Il-4, Il-5, Il-6,Il-7, Il-8, Il′-1, Il′-2, Il′-3, Il′-4, Il′-5, Il′-6, Il′-7 and Il′-8are those of formulae Im-1, Im-2, Im-3, Im-4, Im-5, Im-6, Im-7, Im-8,Im′-1, Im′-2, Im′-3, Im′-4, Im′-5, Im′-6, Im′-7 and Im′-8 respectively:

and pharmaceutically acceptable salts and solvates thereof, wherein:a designates the bond linking R¹ to the piperazine moiety; andR¹, X¹ and X² are as defined above in respect to formula Ib; andR⁵ and R⁶ are as defined above in respect to formula Ie-1; andM¹ and M² are as defined above in respect to formula Ie-3; andR^(12′), R¹³, R¹⁴, R^(14′), R¹⁵, R¹⁸, R¹⁹, R^(19′), R²⁰, R²¹, R^(21′),R²², R^(22′), R²³, R²⁴, R^(24′), R²⁵, R^(25′), R²⁶, R²⁷, R^(27′), R²⁸,R^(28′), R²⁹, R^(29′), R³⁰, R^(30′), R³¹, R^(31′), R³², R^(32′), R³³,R³⁴, R³⁵, X³, X⁵, X⁶; and the two bonds represented by the dotted linesare as defined above in respect to formulae Ig-1, Ig-2, Ig-3, Ig-4,Ig-5, Ig-6, Ig-7 and Ig-8.

In one embodiment, compounds of formulae Im-1, Im-2, Im-3, Im-4, Im-5,Im-6, Im-7, Im-8, Im′-1, Im′-2, Im′-3, Im′-4, Im′-5, Im′-6, Im′-7 andIm′-8 are those wherein X¹ and X² are N.

In another embodiment, compounds of formulae Im-1, Im-2, Im-3, Im-4,Im-5, Im-6, Im-7, Im-8, Im′-1, Im′-2, Im′-3, Im′-4, Im′-5, Im′-6, Im′-7and Im′-8 are those wherein bond a is drawn as a dotted wedge, R¹ isselected from the group consisting of C₁-C₄ alkyl, aryl or aralkylgroup, each of said alkyl, aryl or aralkyl groups being optionallysubstituted by one or more group(s) selected from halo or hydroxyl,and/or X¹ and X² are N.

In yet another embodiment, compounds of Im-1, Im-2, Im-3, Im-4, Im-5,Im-6, Im-7, Im-8, Im′-1, Im′-2, Im′-3, Im′-4, Im′-5, Im′-6, Im′-7 andIm′-8 are those wherein bond a is drawn as a solid wedge, R¹ is selectedfrom the group consisting of C₁-C₄ alkyl, aryl or aralkyl group, each ofsaid alkyl, aryl or aralkyl groups being optionally substituted by oneor more group(s) selected from halo or hydroxyl, and/or X¹ and X² are N.

Other preferred compounds of formula I are those of formulae In, Io, Ipand In′

and pharmaceutically acceptable salts and solvates thereof, wherein:Ar², L¹, L², R¹, R^(1′), R², R^(2′), R³, R^(3′), X¹ and X², are asdefined above in respect to formula I.R⁴, R^(4′), R⁵, R^(5′) and R⁶ are as defined above in respect to formulaId-1;Ar⁴, R⁷ and R^(7′) are as defined above in respect to formulae Id-2 andId-3;M¹ and M² are as defined above in respect to formula Id-4;

Preferred compounds of formulae In, Io and Ip are those wherein R²,R^(2′), R³ and R^(3′) are H.

Still other preferred compounds of formula I are those of formulae Iq,Ir, Is and It

andpharmaceutically acceptable salts and solvates thereof, wherein:Ar¹, L¹, L², R¹, R^(1′), R², R^(2′), R³, R^(3′), X¹ and X², are asdefined above in respect to formula I;R¹¹, R¹², R^(12′) and R¹³ are as defined above in respect to formulaIf-1;Ar⁵, R¹⁴ and X³ are as defined above in respect to formula If-2;Ar⁶ and R¹⁵ are as defined above in respect to formula If-3;R¹⁶ and R¹⁷ are as defined above in respect to formula If-4.

Preferred compounds of formulae Iq, Ir, Is and It are those wherein R²,R^(2′), R³ and R^(3′) are H.

Other preferred compounds of formula I are those of formulae Iu and Iv

and pharmaceutically acceptable salts and solvates thereof, wherein Ar¹,Ar², L¹, L², R¹, R^(1′), R², R^(2′), R³, R^(3′), X¹ and X², are asdefined above in respect to formula I, and R¹ and R^(1′) are different.

Preferred compounds of formulae Iu and Iv are those wherein X¹ and X²are both N.

Still other preferred compounds of formula I are those of formula Iw:

and pharmaceutically acceptable salts and solvates thereof, wherein Ar¹,L¹, L², R¹, R^(1′), R², R^(2′), R³, R^(3′), X¹ and X², are as definedabove in respect to formula I;Ar⁷ and X⁵ are as defined above in respect to formula If-5;

Preferred compounds of formula Iw are those wherein R², R^(2′), R³ andR^(3′) are H.

Still other preferred compounds of formula I are those of formulae Ix,Iy and Iz:

and pharmaceutically acceptable salts and solvates thereof, wherein Ar¹,L¹, L², R¹, R^(1′), R², R^(2′), R³, R^(3′), X¹ and X², are as definedabove in respect to formula I;Ar⁵, Ar⁷, R^(14′), R³⁴, R³⁵, and X⁶ are as defined above in respect toformulae If-6, If-7 and If-8.

Preferred compounds of formula Ix, Iy and Iz are those wherein R²,R^(2′), R³ and R^(3′) are H and/or R^(14′) is H.

Particularly preferred compounds of the invention are those listed inTable 1 hereafter:

TABLE 1 Com- pound (M + n° Name H)⁺ 1(4-fluorophenyl)(3-(pyridin-2-yl)-5,6-dihydro- 324.3[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 2(4-chlorophenyl)(3-(pyridin-2-yl)-5,6-dihydro- 340.8[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 3(3-(4-chlorophenyl)-1H-pyrazol-5-yl)(3-(pyridin-2- 406.8yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 4(3-(3,4-dichlorophenyl)-1H-pyrazol-5-yl)(3-(pyridin- 441.32-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 5(3,4-dichlorophenyl)(3-(pyridin-2-yl)-5,6-dihydro- 375.2[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 6[1,1′-biphenyl]-4-yl(3-(pyridin-2-yl)-5,6-dihydro- 382.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 7(4-fluorophenyl)(3-(quinolin-2-yl)-5,6-dihydro- 374.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 8(4-fluorophenyl)(3-(2-phenylthiazol-4-yl)-5,6-dihydro- 406.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 9(4-fluorophenyl)(3-(2-morpholinothiazol-4-yl)-5,6- 415.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 10(3-(5-chloropyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 358.8a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 11(4-fluorophenyl)(3-(6-methylpyridin-2-yl)-5,6-dihydro- 338.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 12(4-fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro- 338.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 13(3-(2,4-dichlorophenyl)-1H-pyrazol-5-yl)(3-(pyridin-2-yl)- 441.35,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 14(3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3- 455.3(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 15 (4-fluorophenyl)(3-(isoquinolin-3-yl)-5,6-dihydro-374.4 [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 16(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(pyridin-2-yl)-5,6- 400.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 17(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 440.47(8H)-yl)(3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5- yl)methanone 18(3-(4-phenoxyphenyl)-1H-pyrazol-5-yl)(3-(pyridin-2-yl)- 464.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 19[1,1′-biphenyl]-4-yl(3-(quinolin-2-yl)-5,6-dihydro- 432.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 20[1,1′-biphenyl]-4-yl(3-(2-morpholinothiazol-4-yl)-5,6- 473.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 21(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 388.57(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 22(4-fluorophenyl)(3-(8-fluoroquinolin-2-yl)-5,6-dihydro- 392.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 23(3-(8-chloroquinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 408.8a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 24(4-fluorophenyl)(3-(2-(4-(trifluoromethyl)phenyl)thiazol- 474.44-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 25(4-fluorophenyl)(3-(6-phenylpyridin-2-yl)-5,6-dihydro- 400.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 26[1,1′-biphenyl]-4-yl(3-(2-phenylthiazol-4-yl)-5,6-dihydro- 464.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 27(4-fluorophenyl)(3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2- 384.4yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 28(4-fluorophenyl)(3-(2-(3-(trifluoromethyl)phenyl)thiazol- 474.44-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 29(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-5,6-dihydro- 442.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 30(3-(2-(2,3-dichlorophenyl)thiazol-4-yl)-5,6-dihydro- 475.3[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 31(3-(2-(4-chlorophenyl)thiazol-4-yl)-5,6-dihydro- 440.9[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 32(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6- 424.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 33(4-fluorophenyl)(3-(2-(piperidin-1-yl)thiazol-4-yl)-5,6- 413.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 34(4-fluorophenyl)(3-(2-(4-phenylpiperazin-1-yl)thiazol-4- 490.6yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 35(3-(2-(2,4-dichlorophenyl)thiazol-4-yl)-5,6-dihydro- 475.3[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 36(3-(2-(3,5-dichlorophenyl)thiazol-4-yl)-5,6-dihydro- 475.3[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 37(4-fluorophenyl)(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)-5,6- 393.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 38(4-fluorophenyl)(3-(6-morpholinopyridin-2-yl)-5,6- 409.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 39(4-fluorophenyl)(3-(6-(trifluoromethyl)pyridin-2-yl)-5,6- 392.3dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 40(3-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-5,6-dihydro- 466.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 41(4-fluorophenyl)(8-(4-fluorophenyl)-3-(2-phenylthiazol-4- 500.5yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 42(3-(2-(3-chlorophenyl)thiazol-4-yl)-5,6-dihydro- 440.9[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 43(4-fluorophenyl)(8-isopropyl-3-(2-phenylthiazol-4-yl)-5,6- 448.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 44(R)-(4-fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6- 338.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 45(R)-(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)- 420.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 46[1,1′-biphenyl]-4-yl(8-methyl-3-(2-morpholinothiazol-4- 487.6yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 47(4-fluorophenyl)(3-(2-phenyloxazol-4-yl)-5,6-dihydro- 390.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 48(4-fluorophenyl)(8-methyl-3-(2-phenyloxazol-4-yl)-5,6- 404.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 49[1,1′-biphenyl]-4-yl(8-methyl-3-(2-phenyloxazol-4-yl)-5,6- 462.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 50[1,1′-biphenyl]-4-yl(3-(2-phenyloxazol-4-yl)-5,6-dihydro- 448.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 51(4-fluorophenyl)(8-(2-hydroxyethyl)-3-(2-phenylthiazol-4- 450.5yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 52(4-fluorophenyl)(8-methyl-3-(2-morpholinothiazol-4-yl)- 429.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 53(4′-fluoro-[1,1′-biphenyl]-4-yl)(8-methyl-3-(2- 505.6morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 54(3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 470.6a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 55(3-(2-morpholinothiazol-4-yl)-5,6-dihydro- 479.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 56(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro- 493.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 57(4-fluorophenyl)(3-(4-phenylthiazol-2-yl)-5,6-dihydro- 406.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 58(3-(2-(2-chlorophenyl)thiazol-4-yl)-5,6-dihydro- 440.9[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 59(3-(benzo[d]thiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 380.4a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 60(8,8-dimethyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro- 434.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 61(4-fluorophenyl)(8-methyl-3-(quinolin-2-yl)-5,6-dihydro- 388.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 62(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro- 484.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 63(3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 470.6a]pyrazin-7(8H)-yl)(4-(thiophen-3-yl)phenyl)methanone 64(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro- 484.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-3-yl)phenyl)methanone 65 (8-methyl-3-(quinolin-2-yl)-5,6-dihydro- 452.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 66 (3-(2-(2-chlorophenyl)thiazol-4-yl)-5,6-dihydro-505.0 [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 67[1,1′-biphenyl]-4-yl(3-(2-(2-chlorophenyl)thiazol-4-yl)- 499.05,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 68(R)-(3-(2-(4-chlorophenyl)thiazol-4-yl)-8-methyl-5,6- 454.9dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 69(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 438.5a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 70(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8- 438.5methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 71(R)-(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8- 438.5methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 72[1,1′-biphenyl]-4-yl(8-methyl-3-(4-methyl-2- 492.6phenylthiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 73(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro- 488.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 74(3-(2-(2-chlorophenyl)thiazol-4-yl)-8-methyl- 454.95,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 75(4-fluorophenyl)(8-methyl-3-(4-methyl-2-phenylthiazol-5- 434.5yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 76[1,1′-biphenyl]-4-yl(3-(2-(4-fluorophenyl)thiazol-4-yl)-8- 496.6methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 77(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6- 456.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 78(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro- 502.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 79[1,1′-biphenyl]-4-yl(3-(2-(2,4-difluorophenyl)thiazol-4-yl)- 514.68-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone80 (3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6- 520.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 81naphthalen-1-yl(3-(pyridin-2-yl)-5,6-dihydro- 356.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 82(3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3-(pyridin- 420.92-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 83(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)(3-(pyridin- 420.92-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 84(8-methyl-3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro- 469.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 85(8-methyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro- 469.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 86(R)-(3-(2-(4-fluorophenyl)oxazol-4-yl)-8-methyl-5,6- 486.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 872-(7-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro- 410.4[1,2,4]triazolo[4,3-a]pyrazin-3-yl)quinoline 892-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro- 388.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone 90(5-phenylpyridin-2-yl)(3-(quinolin-2-yl)-5,6-dihydro- 433.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 91(6-phenylpyridin-3-yl)(3-(quinolin-2-yl)-5,6-dihydro- 433.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 92(2-phenylpyrimidin-5-yl)(3-(quinolin-2-yl)-5,6-dihydro- 434.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 93(4-phenylcyclohexyl)(3-(quinolin-2-yl)-5,6-dihydro- 438.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 94cyclohexyl(3-(quinolin-2-yl)-5,6-dihydro- 362.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 953-methyl-1-(3-(quinolin-2-yl)-5,6-dihydro- 336.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)butan-1-one 96[1,1′-biphenyl]-2-yl(3-(quinolin-2-yl)-5,6-dihydro- 432.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 97(4-(furan-3-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro- 422.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 98(4-(pyrimidin-5-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro- 434.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 99(9-methyl-9H-carbazol-2-yl)(3-(quinolin-2-yl)-5,6- 459.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 100(4-(pyrimidin-2-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro- 434.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 101(4-(pyrazin-2-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro- 434.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 102(4-(pyridazin-3-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro- 434.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 1034′-(3-(quinolin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- 457.5a]pyrazine-7-carbonyl)-[1,1′-biphenyl]-4-carbonitrile 1041-(4-(3-(quinolin-2-yl)-5,6,7,8-tetrahydro- 453.5[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)phenyl)piperidin-2-one 105(4-morpholinophenyl)(3-(quinolin-2-yl)-5,6-dihydro- 441.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 106(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)(3-(quinolin-2- 450.5yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 107(3-(2-(4-fluorophenyl)thiazol-4-yl)-6-methyl-5,6-dihydro- 502.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 108(3-(2-(4-fluorophenyl)thiazol-4-yl)-5-methyl-5,6-dihydro- 502.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 109(3,4-dichlorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8- 489.4methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 110(3,4-difluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8- 456.5methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 111(3-chloro-4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4- 472.9yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 112(4-chloro-3-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4- 472.9yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 113(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro- 474.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(3,4,5- trifluorophenyl)methanone114 (8-methyl-3-(2-phenyloxazol-4-yl)-5,6-dihydro- 468.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 115(R)-(4-fluorophenyl)(8-methyl-3-(quinolin-2-yl)-5,6- 388.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 117(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(quinolin-2-yl)-5,6- 446.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 118(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(2-morpholinothiazol- 487.64-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 119(R)-(4-fluorophenyl)(8-methyl-3-(6-phenylpyridin-2-yl)- 414.45,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 120(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(2-phenylthiazol-4- 478.6yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 121(R)-(4-fluorophenyl)(8-methyl-3-(4,5,6,7- 398.5tetrahydrobenzo[d]thiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 122(R)-(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6- 456.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 123(R)-(3-(2-(2,3-dichlorophenyl)thiazol-4-yl)-8-methyl-5,6- 489.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 126(R)-(4-fluorophenyl)(8-methyl-3-(2-(4-phenylpiperazin-1- 504.6yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 127(R)-(3-(2-(2,4-dichlorophenyl)thiazol-4-yl)-8-methyl-5,6- 489.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 128(R)-(3-(2-(3-chlorophenyl)thiazol-4-yl)-8-methyl-5,6- 454.9dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 130(R)-(4-fluorophenyl)(8-methyl-3-(2-phenyloxazol-4-yl)- 404.45,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 131(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(2-phenyloxazol-4- 462.5yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 133(R)-(4-fluorophenyl)(8-(2-hydroxyethyl)-3-(2- 450.5phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 134(R)-(4′-fluoro-[1,1′-biphenyl]-4-yl)(8-methyl-3-(2- 505.6morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 135(R)-(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro- 484.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 136 (R)-(8-methyl-3-(2-morpholinothiazol-4-yl)-493.6 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 138(R)-(4-fluorophenyl)(8-methyl-3-(4-phenylthiazol-2-yl)- 420.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 139(R)-(3-(2-(2-chlorophenyl)thiazol-4-yl)-8-methyl-5,6- 454.9dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 142(R)-(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro- 484.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-3-yl)phenyl)methanone 144 (R)-(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-452.5 [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 145(R)-(3-(2-(2-chlorophenyl)thiazol-4-yl)-8-methyl-5,6- 519.1dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 146(R)-[1,1′-biphenyl]-4-yl(3-(2-(2-chlorophenyl)thiazol-4- 513.0yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 149 (R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(4-methyl-2-492.6 phenylthiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 150(R)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6- 502.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 152(R)-[1,1′-biphenyl]-4-yl(3-(2-(4-fluorophenyl)thiazol-4- 496.6yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 155(R)-[1,1′-biphenyl]-4-yl(3-(2-(2,4-difluorophenyl)thiazol- 514.64-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 156(R)-(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6- 520.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 157(8-methyl-3-(2-phenylthiazol-4-yl)-5,6- 483.6dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 158 (8-methyl-3-(2-phenylthiazol-4-yl)-5,6- 483.6dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 159(S)-(4-fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6- 338.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 160(S)-(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8- 438.5methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 161(S)-(4′-fluoro-[1,1′-biphenyl]-4-yl)(8-methyl-3-(2- 505.6morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 162(S)-(4-fluorophenyl)(8-methyl-3-(quinolin-2-yl)-5,6- 388.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 163(S)-(8-methyl-3-(quinolin-2-yl)-5,6-dihydro- 452.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 164(S)-(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8- 438.5methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 165(S)-(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6- 520.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 166(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)-5,6- 420.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 167(S)-(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)- 420.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 168(S)-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8-methyl- 487.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 169(R)-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8-methyl- 487.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 170(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-5,6-dihydro- 506.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 171 (3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-455.5 [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 172(4-fluorophenyl)(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6- 391.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 173(4-fluorophenyl)(3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5,6- 391.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 174(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro- 455.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 175(4-fluorophenyl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5- 409.4yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 176(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6- 473.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 177(3-(3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6- 491.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 178(4-fluorophenyl)(3-(5-phenyl-1H-1,2,4-triazol-3-yl)-5,6- 390.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 179(3-(5-phenyl-1H-1,2,4-triazol-3-yl)-5,6-dihydro- 454.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 180(4-fluorophenyl)(3-(2-(2-fluorophenyl)thiazol-4-yl)-5,6- 424.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 181(3-(2-(2-fluorophenyl)thiazol-4-yl)-5,6-dihydro- 488.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 182[1,1′-biphenyl]-4-yl(3-(2-(2-fluorophenyl)thiazol-4-yl)- 482.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 183(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(2-(2- 500.5fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 185(3-(3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6- 491.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 186[1,1′-biphenyl]-4-yl(3-(2-((4,5-dichloro-1H-imidazol-1- 537.4yl)methyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 187(3-(2-((4,5-dichloro-1H-imidazol-1-yl)methyl)thiazol-4- 555.4yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4′-fluoro-[1,1′-biphenyl]-4-yl)methanone 188(3-(2-(4-chlorobenzyl)thiazol-4-yl)-5,6-dihydro- 454.9[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone 189(3-(2-(4-chlorobenzyl)thiazol-4-yl)-5,6-dihydro- 519.1[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 190(4-fluorophenyl)(3-(2-(p-tolyl)thiazol-4-yl)-5,6-dihydro- 420.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 191(4-(thiophen-2-yl)phenyl)(3-(2-(p-tolyl)thiazol-4-yl)-5,6- 484.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 192[1,1′-biphenyl]-4-yl(3-(2-(p-tolyl)thiazol-4-yl)-5,6- 478.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 193(4-fluorophenyl)(3-(2-(thiophen-2-yl)thiazol-4-yl)-5,6- 412.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 194(4-(thiophen-2-yl)phenyl)(3-(2-(thiophen-2-yl)thiazol-4- 476.6yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 195[1,1′-biphenyl]-4-yl(3-(2-(thiophen-2-yl)thiazol-4-yl)-5,6- 470.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 196(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(2- 488.6(thiophen-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 198(3-(2-(((4-chlorophenyl)sulfonyl)methyl)thiazol-4-yl)-5,6- 583.1dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 199 [1,1′-biphenyl]-4-yl(3-(2-(((4-577.1 chlorophenyl)sulfonyl)methyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 200(3-(2-(((4-chlorophenyl)sulfonyl)methyl)thiazol-4-yl)-5,6- 595.1dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4′-fluoro-[1,1′-biphenyl]-4-yl)methanone 201(4-fluorophenyl)(3-(2-(2-methoxyphenyl)thiazol-4-yl)-5,6- 436.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 202(3-(2-(2-methoxyphenyl)thiazol-4-yl)-5,6-dihydro- 500.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 203[1,1′-biphenyl]-4-yl(3-(2-(2-methoxyphenyl)thiazol-4-yl)- 494.65,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 204[1,1′-biphenyl]-4-yl(3-(3-(4-fluorophenyl)-1,2,4- 467.5oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 205(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(3-(4-fluorophenyl)- 485.51,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 206(4-fluorophenyl)(3-(2-(3-fluorophenyl)thiazol-4-yl)-5,6- 424.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 207(3-(2-(3-fluorophenyl)thiazol-4-yl)-5,6-dihydro- 488.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 208(4-fluorophenyl)(3-(2-isopropylthiazol-4-yl)-5,6-dihydro- 372.4[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 209(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8-methyl- 487.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 211(3-(3-phenyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro- 471.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 212(4-fluorophenyl)(3-(3-phenyl-1,2,4-thiadiazol-5-yl)-5,6- 407.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 213(3-(2-(4-bromophenyl)thiazol-4-yl)-5,6-dihydro- 549.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 214 (3-(2-(4-bromophenyl)thiazol-4-yl)-5,6-dihydro-485.3 [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4- fluorophenyl)methanone215 (3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6- 516.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(5-methylthiophen-2-yl)phenyl)methanone 2164-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6,7,8- 445.5tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7- carbonyl)benzonitrile 217[1,1′-biphenyl]-4-yl(3-(3-phenyl-1,2,4-oxadiazol-5-yl)- 449.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 218(4-fluorophenyl)(3-(2-(pyridin-4-yl)thiazol-4-yl)-5,6- 407.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 219(3-(2-(quinolin-2-yl)thiazol-4-yl)-5,6-dihydro- 521.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 220(3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro- 467.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 221(3-(2-(4-(dimethylamino)phenyl)thiazol-4-yl)-5,6- 449.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 222(3-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-5,6-dihydro- 467.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 223(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(3-phenyl-1,2,4- 467.5oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 224(3-(2-(pyridin-2-yl)thiazol-4-yl)-5,6-dihydro- 471.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 225(4-fluorophenyl)(3-(1-methyl-3-phenyl-1H-pyrazol-5- 403.4yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 226(3-(2-(pyrimidin-2-yl)thiazol-4-yl)-5,6-dihydro- 472.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 227(S)-(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro- 493.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 228 (3-(2-(pyridin-4-yl)thiazol-4-yl)-5,6-dihydro-471.6 [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 229(3-(2-(4-(dimethylamino)phenyl)thiazol-4-yl)-5,6- 513.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 230(4-fluorophenyl)(3-(2-(pyridin-2-yl)thiazol-4-yl)-5,6- 407.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 231phenyl(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 306.3a]pyrazin-7(8H)-yl)methanone 232(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 320.4a]pyrazin-7(8H)-yl)(p-tolyl)methanone 233(S)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6- 516.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(2-methylthiophen-3-yl)phenyl)methanone 234(R)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6- 516.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(2-methylthiophen-3-yl)phenyl)methanone 235(3-(2-(pyrazin-2-yl)thiazol-4-yl)-5,6-dihydro- 472.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 2364-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro- 495.6[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2- yl)benzonitrile 237(4-fluorophenyl)(3-(2-(pyrazin-2-yl)thiazol-4-yl)-5,6- 408.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 238(4-fluorophenyl)(3-(1-methyl-5-phenyl-1H-pyrazol-3- 403.4yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 239(3-(2-(4-morpholinophenyl)thiazol-4-yl)-5,6-dihydro- 555.7[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 240(4-fluorophenyl)(3-(2-(4-morpholinophenyl)thiazol-4- 491.6yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 241(3-(2-(4-(4-methylpiperazin-1-yl)phenyl)thiazol-4-yl)- 568.75,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 242(4-fluorophenyl)(3-(2-(4-(4-methylpiperazin-1- 504.6yl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 243(3-(2-(4-(piperidin-1-yl)phenyl)thiazol-4-yl)-5,6-dihydro- 553.7[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 244(4-fluorophenyl)(3-(2-(4-(piperidin-1-yl)phenyl)thiazol- 489.64-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 245(3-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-4-yl)-5,6- 539.7dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 246(4-fluorophenyl)(3-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol- 475.64-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 247(3-(2-(piperidin-1-yl)thiazol-4-yl)-5,6-dihydro- 477.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 248(3-(2-(pyrrolidin-1-yl)thiazol-4-yl)-5,6-dihydro- 463.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 249(4-fluorophenyl)(3-(2-(pyrrolidin-1-yl)thiazol-4-yl)-5,6- 399.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 250(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)-5,6-dihydro- 492.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 251(4-fluorophenyl)(3-(2-(4-methylpiperazin-1-yl)thiazol-4- 428.5yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 252(3-(1-methyl-2-phenyl-1H-imidazol-4-yl)-5,6-dihydro- 467.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 253(4-(dimethylamino)phenyl)(3-(2-(4-fluorophenyl)thiazol- 449.54-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 254(3-(1-(2-methoxyethyl)-3-phenyl-1H-pyrazol-5-yl)-5,6- 511.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 255(4-fluorophenyl)(3-(1-(2-methoxyethyl)-3-phenyl-1H- 447.5pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 256(3-(2-isobutylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo 450.6[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2- yl)phenyl)methanone 257(3-(2-(2-(2-methoxyethyl)morpholino)thiazol-4-yl)-5,6- 537.7dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 258(3-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-5,6- 449.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 259(4-fluorophenyl)(3-(2-isobutylthiazol-4-yl)-5,6-dihydro- 386.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 260(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6- 423.5dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)methanone 261(3-(2-(2,5-dimethylmorpholino)thiazol-4-yl)-5,6-dihydro- 507.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 262(3-(2-(2-hydroxyphenyl)thiazol-4-yl)-5,6-dihydro- 486.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 263(3-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-5,6- 513.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 265(3-(2-(2,6-dimethylmorpholino)thiazol-4-yl)-5,6-dihydro- 507.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 266(3-(2-(2,2-dimethylmorpholino)thiazol-4-yl)-5,6-dihydro- 507.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 267 (3-(3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro- 453.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 268(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6- 516.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(3-methylthiophen-2-yl)phenyl)methanone 269(4-fluorophenyl)(3-(3-phenyl-1H-pyrazol-5-yl)-5,6- 389.4dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 270(R)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl- 516.65,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(3-methylthiophen-2-yl)phenyl)methanone 271(4-fluorophenyl)(3-(2-(2-hydroxyphenyl)thiazol-4- 422.4yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 272(S)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6- 516.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(3-methylthiophen-2-yl)phenyl)methanone 273(3-(2-(2-methylmorpholino)thiazol-4-yl)-5,6-dihydro- 493.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 274(3-(2-(4,4-dimethylpiperidin-1-yl)thiazol-4-yl)-5,6- 505.7dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 275(3-(5-methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3- 408.5a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 276(3-(2-(4,4-dimethylpiperidin-1-yl)thiazol-4-yl)-5,6- 441.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 277(4-fluorophenyl)(3-(2-(2-(methoxymethyl)piperidin-1- 457.5yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 278(4-fluorophenyl)(8-methyl-3-(6-methylpyridin-2-yl)- 352.45,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)methanone 279(3-(2-(2-(methoxymethyl)piperidin-1-yl)thiazol-4-yl)- 521.75,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 280 tert-butyl(2-(2-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8- 629.8tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenoxy)ethyl)carbamate 281(3-(2-(2-(2-hydroxyethoxy)phenyl)thiazol-4-yl)-5,6- 530.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 282(3-(2-(2-(2-aminoethoxy)phenyl)thiazol-4-yl)-5,6- 529.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 283N-(4-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro- 563.7[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenyl)methanesulfonamide 284(3-(1-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-5-yl)-5,6- 497.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 285(3-(1-(2-hydroxyethyl)-5-phenyl-1H-pyrazol-3-yl)-5,6- 497.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 286[1,1′-biphenyl]-4-yl(8-methyl-3-(6-methylpyridin-2-yl)- 410.55,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone 287(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro- 416.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 288(3-(2-(2,4-difluorophenyl)-5-methylthiazol-4-yl)-5,6- 520.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 289(3-(2-(3-(dimethylamino)phenyl)thiazol-4-yl)-5,6- 513.6dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 290(3-(2-(3-(dimethylamino)phenyl)thiazol-4-yl)-5,6- 449.5dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone 291N-(3-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8- 563.7tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenyl)methanesulfonamide 292N-(2-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro- 563.7[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenyl)methanesulfonamide 293(3-(quinolin-2-yl)-5,6-dihydroimidazo[1,2-a]pyrazin- 437.57(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 294(3-(4-chlorophenyl)-1H-pyrazol-5-yl)(3-(2-(4- 507.0fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 295(3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3-(2-(4- 521.0fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 296(3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3-(2- 555.4(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 297(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)(3-(2-(4- 521.0fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone 298 tert-butyl(2-(3-phenyl-5-(7-(4-(thiophen-2-yl)benzoyl)- 596.75,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate 299 tert-butyl(2-(5-phenyl-3-(7-(4-(thiophen-2-yl)benzoyl)- 596.75,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate 300(3-(2-(2-bromophenyl)thiazol-4-yl)-5,6-dihydro- 549.5[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 301 (3-(2-(3-bromophenyl)thiazol-4-yl)-5,6-dihydro-549.5 [1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone 3022-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro- 495.6[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl) benzonitrile 3033-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7 ,8-tetrahydro- 495.6[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl) benzonitrile 304(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro- 516.6[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(2-methylthiophen-3-yl)phenyl)methanone

The compounds of table 1 were named using ChemDraw Ultra 12 purchasedfrom CambridgeSoft (Cambridge, Mass., USA).

The compounds of formula I can be prepared by different ways withreactions known by the person skilled in the art. Reaction schemes asdescribed in the example section illustrate by way of example differentpossible approaches.

The invention further provides the use of the compounds of the inventionor pharmaceutically acceptable salts, or solvates thereof as antagonistsof NK-3 receptor.

Accordingly, in a particularly preferred embodiment, the inventionrelates to the use of compounds of formula I and subformulae inparticular those of table 1 above, or pharmaceutically acceptable saltsand solvates thereof, as NK-3 receptor antagonists.

[Applications]

The compounds of the invention are therefore useful as medicaments, inparticular in the prevention and/or treatment of depression, anxiety,pyschosis, schizophrenia, psychotic disorders, bipolar disorders,cognitive disorders, Parkinson's disease, Alzheimer's disease, attentiondeficit hyperactivity disorder (ADHD), pain, convulsion, obesity,inflammatory diseases including irritable bowel syndrome andinflammatory bowel disorders, emesis, pre-eclampsia, airway relateddiseases including chronic obstructive pulmonary disease, asthma, airwayhyperresponsiveness, bronchoconstriction and cough, reproductiondisorders and sex hormone-dependent diseases including but not limitedto benign prostatic hyperplasia (BPH), metastatic prostatic carninoma,testicular cancer, breast cancer, androgen dependent acne, male patternbaldness, endometriosis, abnormal puberty, uterine fibrosis,hormone-dependent cancers, hyperandrogenism, hirsutism, virilization,polycystic ovary syndrome (PCOS), HAIR-AN syndrome (hyperandrogenism,insulin resistance and acanthosis nigricans), ovarian hyperthecosis(HAIR-AN with hyperplasia of luteinized theca cells in ovarian stroma),other manifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility) and androgen-producingtumor (virilizing ovarian or adrenal tumor).

The invention also provides for a method for delaying in patient theonset of depression, anxiety, pyschosis, schizophrenia, psychoticdisorders, bipolar disorders, cognitive disorders, Parkinson's disease,Alzheimer's disease, attention deficit hyperactivity disorder (ADHD),pain, convulsion, obesity, inflammatory diseases including irritablebowel syndrome and inflammatory bowel disorders, emesis, pre-eclampsia,airway related diseases including chronic obstructive pulmonary disease,asthma, airway hyperresponsiveness, bronchoconstriction and cough,reproduction disorders and sex hormone-dependent diseases including butnot limited to benign prostatic hyperplasia (BPH), metastatic prostaticcarninoma, testicular cancer, breast cancer, androgen dependent acne,male pattern baldness, endometriosis, abnormal puberty, uterinefibrosis, hormone-dependent cancers, hyperandrogenism, hirsutism,virilization, polycystic ovary syndrome (PCOS), HAIR-AN syndrome(hyperandrogenism, insulin resistance and acanthosis nigricans), ovarianhyperthecosis (HAIR-AN with hyperplasia of luteinized theca cells inovarian stroma), other manifestations of high intraovarian androgenconcentrations (e.g. follicular maturation arrest, atresia, anovulation,dysmenorrhea, dysfunctional uterine bleeding, infertility) andandrogen-producing tumor (virilizing ovarian or adrenal tumor)comprising the administration of a pharmaceutically effective amount ofa compound of formula (I) or pharmaceutically acceptable salt thereof toa patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

The compounds of the invention are also useful in the treatment ofgynecological disorders and infertility. In particular, the inventionprovides methods to suppress the LH-surge in assisted conception.

The compounds of the invention are also useful to cause male castrationand to inhibit the sex drive in men. This of particular interest in thetreatment of male sexual offenders. The invention further provides theuse of a compound of formula (I) or a pharmaceutically acceptable saltor solvate thereof for the manufacture of a medicament for treatingand/or preventing depression, anxiety, pyschosis, schizophrenia,psychotic disorders, bipolar disorders, cognitive disorders, Parkinson'sdisease, Alzheimer's disease, attention deficit hyperactivity disorder(ADHD), pain, convulsion, obesity, inflammatory diseases includingirritable bowel syndrome and inflammatory bowel disorders, emesis,pre-eclampsia, airway related diseases including chronic obstructivepulmonary disease, asthma, airway hyperresponsiveness,bronchoconstriction and cough, reproduction disorders and sexhormone-dependent diseases including but not limited to benign prostatichyperplasia (BPH), metastatic prostatic carninoma, testicular cancer,breast cancer, androgen dependent acne, male pattern baldness,endometriosis, abnormal puberty, uterine fibrosis, hormone-dependentcancers, hyperandrogenism, hirsutism, virilization, polycystic ovarysyndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin resistanceand acanthosis nigricans), ovarian hyperthecosis (HAIR-AN withhyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility) and androgen-producingtumor (virilizing ovarian or adrenal tumor) in a patient.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

The invention further provides the use of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament to suppress the LH-surge in assisted conception in apatient. Preferably the patient is a warm-blooded animal, morepreferably a woman.

The invention further provides the use of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for the manufactureof a medicament to cause male castration and to inhibit the sex drive inmen. This is of particular interest in the treatment of male sexualoffenders.

According to a further feature of the present invention there isprovided a method for modulating NK-3 receptor activity, in a patient,preferably a warm blooded animal, and even more preferably a human, inneed of such treatment, which comprises administering to said patient aneffective amount of compound of the present invention, or apharmaceutically acceptable salt or solvate thereof.

According to one embodiment, the compounds of the invention, theirpharmaceutical acceptable salts or solvates may be administered as partof a combination therapy. Thus, are included within the scope of thepresent invention embodiments comprising coadministration of, andcompositions and medicaments which contain, in addition to a compound ofthe present invention, a pharmaceutically acceptable salt or solvatethereof as active ingredient, additional therapeutic agents and/oractive ingredients. Such multiple drug regimens, often referred to ascombination therapy, may be used in the treatment and/or prevention ofany of the diseases or conditions mediated by or associated with NK-3receptor modulation. The use of such combinations of therapeutic agentsis especially pertinent with respect to the treatment of theabove-mentioned disorders within a patient in need of treatment or oneat risk of becoming such a patient.

In addition to the requirement of therapeutic efficacy, which maynecessitate the use of active agents in addition to the NK-3 receptormodulator compounds of Formula I or pharmaceutical acceptable salts orsolvates thereof, there may be additional rationales which compel orhighly recommend the use of combinations of drugs involving activeingredients which represent adjunct therapy, i.e., which complement andsupplement the function performed by the NK-3 receptor modulatorcompounds of the present invention. Suitable supplementary therapeuticagents used for the purpose of auxiliary treatment include drugs which,instead of directly treating or preventing a disease or conditionmediated by or associated with NK-3 receptor modulation, treat diseasesor conditions which directly result from or indirectly accompany thebasic or underlying NK-3 receptor modulated disease or condition.

According to a further feature of the present invention the compound ofFormula I, a pharmaceutically acceptable salt or solvate thereof may beused in combination therapy with antipsychotic drugs (APD), to improvethe efficacy and to minimize secondary effects associated to APDincluding but not limited to Dopamine 2/3 and 5-HT2 receptorsantagonists. More particular the compound of Formula I, apharmaceutically acceptable salt or solvate thereof may be used as anadjunct therapy in combination with an atypical antipsychotic drug,including but not limited to risperidone, clozapine, olanzapine, wherethe NK-3 receptor modulator may serve a role as dose-limiting for theatypical antipsychotic and therefore spare the patient from some of theside effect of those atypical antipsychotic drugs.

Thus, the methods of treatment and pharmaceutical compositions of thepresent invention may employ the compounds of Formula I orpharmaceutical acceptable salts or solvates thereof in the form ofmonotherapy, but said methods and compositions may also be used in theform of multiple therapy in which one or more compounds of Formula I ortheir pharmaceutically acceptable salts or solvates are coadministeredin combination with one or more other therapeutic agents.

In the above-described embodiment combinations of the present invention,the compound of Formula I, a pharmaceutically acceptable salt or solvatethereof and other therapeutic active agents may be administered in termsof dosage forms either separately or in conjunction with each other, andin terms of their time of administration, either serially orsimultaneously. Thus, the administration of one component agent may beprior to, concurrent with, or subsequent to the administration of theother component agent(s).

The invention also provides pharmaceutical compositions comprising acompound of formula I or a pharmaceutically acceptable salt or solvatethereof and at least one pharmaceutically acceptable carrier, diluent,excipient and/or adjuvant. As indicated above, the invention also coverspharmaceutical compositions which contain, in addition to a compound ofthe present invention, a pharmaceutically acceptable salt or solvatethereof as active ingredient, additional therapeutic agents and/oractive ingredients.

Another object of this invention is a medicament comprising at least onecompound of the invention, or a pharmaceutically acceptable salt orsolvate thereof, as active ingredient.

According to a further feature of the present invention there isprovided the use of a compound of formula I or a pharmaceuticallyacceptable salt or solvate thereof for the manufacture of a medicamentfor modulating NK-3 receptor activity in a patient, in need of suchtreatment, which comprises administering to said patient an effectiveamount of compound of the present invention, or a pharmaceuticallyacceptable salt or solvate thereof.

Preferably, the patient is a warm-blooded animal, more preferably ahuman.

As set forth above, the compounds of the invention, theirpharmaceutically acceptable salts or solvates may be used in monotherapyor in combination therapy. Thus, according to one embodiment, theinvention provides the use of a compound of the invention for themanufacture of a medicament for at least one of the purposes describedabove, wherein said medicament is administered to a patient in needthereof, preferably a warm-blooded animal, and even more preferably ahuman, in combination with at least one additional therapeutic agentand/or active ingredient. The benefits and advantages of such a multipledrug regimen, possible administration regimens as well as suitableadditional therapeutic agents and/or active ingredients are thosedescribed above.

Generally, for pharmaceutical use, the compounds of the inventions maybe formulated as a pharmaceutical preparation comprising at least onecompound of the invention and at least one pharmaceutically acceptablecarrier, diluent, excipient and/or adjuvant, and optionally one or morefurther pharmaceutically active compounds.

By means of non-limiting examples, such a formulation may be in a formsuitable for oral administration, for parenteral administration (such asby intravenous, intramuscular or subcutaneous injection or intravenousinfusion), for topical administration (including ocular), foradministration by inhalation, by a skin patch, by an implant, by asuppository, etc. Such suitable administration forms—which may be solid,semi-solid or liquid, depending on the manner of administration—as wellas methods and carriers, diluents and excipients for use in thepreparation thereof, will be clear to the skilled person; reference ismade to the latest edition of Remington's Pharmaceutical Sciences.

Some preferred, but non-limiting examples of such preparations includetablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes,lotions, soft and hard gelatin capsules, suppositories, drops, sterileinjectable solutions and sterile packaged powders (which are usuallyreconstituted prior to use) for administration as a bolus and/or forcontinuous administration, which may be formulated with carriers,excipients, and diluents that are suitable per se for such formulations,such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethyleneglycol, cellulose, (sterile) water, methylcellulose, methyl- andpropylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetableoils and mineral oils or suitable mixtures thereof. The formulations canoptionally contain other substances that are commonly used inpharmaceutical formulations, such as lubricating agents, wetting agents,emulsifying and suspending agents, dispersing agents, desintegrants,bulking agents, fillers, preserving agents, sweetening agents, flavoringagents, flow regulators, release agents, etc. The compositions may alsobe formulated so as to provide rapid, sustained or delayed release ofthe active compound(s) contained therein.

The pharmaceutical preparations of the invention are preferably in aunit dosage form, and may be suitably packaged, for example in a box,blister, vial, bottle, sachet, ampoule or in any other suitablesingle-dose or multi-dose holder or container (which may be properlylabeled); optionally with one or more leaflets containing productinformation and/or instructions for use. Generally, such unit dosageswill contain between 0.05 and 1000 mg, and usually between 1 and 500 mg,of the at least one compound of the invention, e.g. about 10, 25, 50,100, 200, 300 or 400 mg per unit dosage.

Usually, depending on the condition to be prevented or treated and theroute of administration, the active compound of the invention willusually be administered between 0.01 to 100 mg per kilogram, more oftenbetween 0.1 and 50 mg, such as between 1 and 25 mg, for example about0.5, 1, 5, 10, 15, 20 or 25 mg, per kilogram body weight of the patientper day, which may be administered as a single daily dose, divided overone or more daily doses, or essentially continuously, e.g. using a dripinfusion.

Definitions

The definitions and explanations below are for the terms as usedthroughout the entire application, including both the specification andthe claims.

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless indicatedotherwise.

Where groups may be substituted, such groups may be substituted with oneor more substituents, and preferably with one, two or threesubstituents. Substituents may be selected from but not limited to, forexample, the group comprising halogen, hydroxyl, oxo, nitro, amido,carboxy, amino, cyano haloalkoxy, and haloalkyl.

As used herein the terms such as “alkyl, aryl, or cycloalkyl, each beingoptionally substituted with . . . ” or “alkyl, aryl, or cycloalkyl,optionally substituted with . . . ” encompasses “alkyl optionallysubstituted with . . . ”, “aryl optionally substituted with . . . ” and“cycloalkyl optionally substituted with . . . ”.

The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.Preferred halo groups are fluoro and chloro.

The term “alkyl” by itself or as part of another substituent refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numbergreater than or equal to 1. Generally, alkyl groups of this inventioncomprise from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms,more preferably from 1 to 3 carbon atoms, still more preferably 1 to 2carbon atoms. Alkyl groups may be linear or branched and may besubstituted as indicated herein.

Suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl and t-butyl, pentyl and its isomers (e.g.n-pentyl, iso-pentyl), and hexyl and its isomers (e.g. n-hexyl,iso-hexyl). Preferred alkyl groups include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. C_(x-y)-alkyl andCx-Cy-alkyl refer to alkyl groups which comprise from x to y carbonatoms.

When the suffix “ene” (“alkylene”) is used in conjunction with an alkylgroup, this is intended to mean the alkyl group as defined herein havingtwo single bonds as points of attachment to other groups. The term“alkylene” includes methylene, ethylene, methylmethylene, propylene,ethylethylene, and 1,2-dimethylethylene.

The term “haloalkyl” alone or in combination, refers to an alkyl radicalhaving the meaning as defined above wherein one or more hydrogens arereplaced with a halogen as defined above. Non-limiting examples of suchhaloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and the like.C_(x-y)-haloalkyl and Cx-Cy-alkyl refer to alkyl groups which comprisefrom x to y carbon atoms. Preferred haloalkyl groups are difluoromethyl,trifluoromethyl.

The term “cycloalkyl” as used herein is a cyclic alkyl group, that is tosay, a monovalent, saturated, or unsaturated hydrocarbyl group having 1or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclichydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbonatoms in the ring and generally, according to this invention comprisefrom 3 to 10, more preferably from 3 to 8 carbon atoms still morepreferably from 3 to 6 carbon atoms. Examples of cycloalkyl groupsinclude but are not limited to cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, with cyclopropyl being particularly preferred.

When the suffix “ene” is used in conjunction with a cyclic group, thisis intended to mean the cyclic group as defined herein having two singlebonds as points of attachment to other groups.

Therefore, “cycloalkylene” herein refers to a saturated homocyclichydrocarbyl biradical of Formula C_(n)H_(2n-2). Suitable cycloalkylenegroups are C₃₋₆ cycloalkylene group, preferably a C₃₋₅ cycloalkylene(i.e. 1,2-cyclopropylene, 1,1-cyclopropylene, 1,1-cyclobutylene,1,2-cyclobutylene, 1,3-cyclobutylene, 1,3-cyclopentylene, or1,1-cyclopentylene), more preferably a C₃₋₄ cycloalkylene (i.e.1,2-cyclopropylene, 1,1-cyclopropylene, 1,1-cyclobutylene,1,2-cyclobutylene).

Where at least one carbon atom in a cycloalkyl group is replaced with aheteroatom, the resultant ring is referred to herein as“heterocycloalkyl” or “heterocyclyl”.

The terms “heterocyclyl”, “heterocycloalkyl” or “heterocyclo” as usedherein by itself or as part of another group refer to non-aromatic,fully saturated or partially unsaturated cyclic groups (for example, 3to 7 member monocyclic, 7 to 11 member bicyclic, or containing a totalof 3 to 10 ring atoms) which have at least one heteroatom in at leastone carbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen, oxygen and/or sulfur atoms, where the nitrogen and sulfurheteroatoms may optionally be oxidized and the nitrogen heteroatoms mayoptionally be quaternized. Any of the carbon atoms of the heterocyclicgroup may be substituted by oxo (for example piperidone, pyrrolidinone).The heterocyclic group may be attached at any heteroatom or carbon atomof the ring or ring system, where valence allows. The rings ofmulti-ring heterocycles may be fused, bridged and/or joined through oneor more spiro atoms. Non limiting exemplary heterocyclic groups includeoxetanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinylimidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl,thiazolidinyl, isothiazolidinyl, piperidinyl, 3H-indolyl, indolinyl,isoindolinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl,2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl,4H-pyranyl, 3,4-dihydro-2H-pyranyl, 3-dioxolanyl, 1,4-dioxanyl,2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl,tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl,tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl,thiomorpholin-4-yl, thiomorpholin-4-ylsulfoxide,thiomorpholin-4-ylsulfone, 1,3-dioxolanyl, 1,4-oxathianyl,1H-pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl,and morpholin-4-yl.

The ring atoms of selected heterocyclyl and heterocyclylene moieties arenumbered based on scheme below

The ring atoms of fused piperazine of the invention are numbered basedon scheme below

The term “aryl” as used herein refers to a polyunsaturated, aromatichydrocarbyl group having a single ring (i.e. phenyl) or multiplearomatic rings fused together (e.g. naphtyl) or linked covalently,typically containing 5 to 12 atoms; preferably 6 to 10, wherein at leastone ring is aromatic. The aromatic ring may optionally include one totwo additional rings (either cycloalkyl, heterocyclyl or heteroaryl)fused thereto. Aryl is also intended to include the partiallyhydrogenated derivatives of the carbocyclic systems enumerated herein.Non-limiting examples of aryl comprise phenyl, biphenylyl, biphenylenyl,5- or 6-tetralinyl, naphthalen-1- or -2-yl, 4-, 5-, 6 or 7-indenyl, 1-2-, 3-, 4- or 5-acenaphtylenyl, 3-, 4- or 5-acenaphtenyl, 1- or2-pentalenyl, 4- or 5-indanyl, 5-, 6-, 7- or 8-tetrahydronaphthyl,1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, 1-, 2-, 3-, 4- or5-pyrenyl.

The term “arylene” as used herein is intended to include divalentcarbocyclic aromatic ring systems such as phenylene, biphenylylene,naphthylene, indenylene, pentalenylene, azulenylene and the like.Arylene is also intended to include the partially hydrogenatedderivatives of the carbocyclic systems enumerated above. Non-limitingexamples of such partially hydrogenated derivatives are1,2,3,4-tetrahydronaphthylene, 1,4-dihydronaphthylene and the like.

Where at least one carbon atom in an aryl group is replaced with aheteroatom, the resultant ring is referred to herein as a heteroarylring.

The term “heteroaryl” as used herein by itself or as part of anothergroup refers but is not limited to 5 to 12 carbon-atom aromatic rings orring systems containing 1 to 2 rings which are fused together or linkedcovalently, typically containing 5 to 6 atoms; at least one of which isaromatic, in which one or more carbon atoms in one or more of theserings is replaced by oxygen, nitrogen and/or sulfur atoms where thenitrogen and sulfur heteroatoms may optionally be oxidized and thenitrogen heteroatoms may optionally be quaternized. Such rings may befused to an aryl, cycloalkyl, heteroaryl or heterocyclyl ring.Non-limiting examples of such heteroaryl, include: furanyl, thiophenyl,pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl,thiatriazolyl, pyridinyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl,dioxinyl, thiazinyl, triazinyl, imidazo[2,1-b][1,3]thiazolyl,thieno[3,2-b]furanyl, thieno[3,2-b]thiophenyl,thieno[2,3-d][1,3]thiazolyl, thieno[2,3-d]imidazolyl,tetrazolo[1,5-a]pyridinyl, indolyl, indolizinyl, isoindolyl,benzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl,indazolyl, benzimidazolyl, 1,3-benzoxazolyl, 1,2-benzisoxazolyl,2,1-benzisoxazolyl, 1,3-benzothiazolyl, 1,2-benzoisothiazolyl,2,1-benzoisothiazolyl, benzotriazolyl, 1,2,3-benzoxadiazolyl,2,1,3-benzoxadiazolyl, 1,2,3-benzothiadiazolyl, 2,1,3-benzothiadiazolyl,thienopyridinyl, purinyl, imidazo[1,2-a]pyridinyl, 6-oxo-pyridazin-1(6H)-yl, 2-oxopyridin-1 (2H)-yl, 6-oxo-pyridazin-1 (6H)-yl,2-oxopyridin-1(2H)-yl, 1,3-benzodioxolyl, quinolinyl, isoquinolinyl,cinnolinyl, quinazolinyl, quinoxalinyl.

The term “heteroarylene” as used herein means divalent carbocyclicaromatic ring systems including pyridinylene and the like.

The ring atoms of selected heteroaryl or heteroarylene moieties arenumbered on scheme below:

The term “biaryl” as used herein designates two aryl moieties as definedherein linked via a single bond. Non-limiting examples of such biarylmoieties include all biphenyl regioisomers 2-biphenyl, 3-biphenyl and4-biphenyl.

The term “heterobiaryl” as used herein designates two heteroarylmoieties as defined herein or a heteroaryl moiety and an aryl moity asdefined herein linked via a single bond. Non-limiting examples of suchheterobiaryl moieties are given hereunder.

The term “carbamoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The term “carbamimidoyl” as used herein means a group of formula

wherein the arrow defines the attachment point.

The compounds of Formula I and subformulae thereof contain at least oneasymmetric center and thus may exist as different stereoisomeric forms.Accordingly, the present invention includes all possible stereoisomersand includes not only racemic compounds but the individual enantiomersand their non racemic mixtures as well. When a compound is desired as asingle enantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as each are known in the art. Resolutionof the final product, an intermediate, or a starting material may beeffected by any suitable method known in the art. See, for example,Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L.N. Mander (Wiley-Interscience, 1994), incorporated by reference withregard to stereochemistry.

The bonds from an asymmetric carbon in compounds of the presentinvention may be depicted herein using a solid line (

), a zigzag line (

), a solid wedge (

), or a dotted wedge (

). The use of a solid line to depict bonds from an asymmetric carbonatom is meant to indicate that all possible stereoisomers in anyrelative ratio are meant to be included, unless it is clear from thecontext that a specific stereoisomer is intended. As a non limitingexample, a solid line depicting bonds from an asymmetric carbon atom ina compound containing one asymmetric carbon encompasses a racemicmixture of both enantiomers. The term racemic used herein indicated a1/1 ratio between the two enantiomers. The use of either a solid ordotted wedge to depict bonds from an asymmetric carbon atom is meant toindicate that only the stereoisomer shown is meant to be included.

As a non limiting example, compounds of formula Ic wherein R^(1′) is H,R is not H and bond a, which designates the bond linking R¹ to thepiperazine moiety, is drawn as a dotted wedge are stereoisomers offormula A. Compounds of formula Ic wherein R^(1′) is H, R¹ is not H andbond a is drawn as a solid wedge are stereoisomers of formula B.

The compounds of the invention may also contain more than one asymmetriccarbon atom. In those compounds, the use of a solid line to depict bondsfrom asymmetric carbon atoms is meant to indicate that all possiblestereoisomers in any relative ratio are meant to be included, unless itis clear from the context that a specific stereoisomer is intended.

The compounds of the invention may be in the form of pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts of the compounds offormula I include the acid addition and base salts thereof. Suitableacid addition salts are formed from acids which form non-toxic salts.Examples include the acetate, adipate, aspartate, benzoate, besylate,bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate,cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate,saccharate, stearate, succinate, tannate, tartrate, tosylate,trifluoroacetate and xinofoate salts. Suitable base salts are formedfrom bases which form non-toxic salts. Examples include the aluminium,arginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine,4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids andbases may also be formed, for example, hemisulphate and hemicalciumsalts. Preferred, pharmaceutically acceptable salts includehydrochloride/chloride, hydrobromide/bromide, bisulphate/sulphate,nitrate, citrate, and acetate.

When the compounds of the invention contain an acidic group as well as abasic group the compounds of the invention may also form internal salts,and such compounds are within the scope of the invention. When thecompounds of the invention contain a hydrogen-donating heteroatom (e.g.NH), the invention also covers salts and/or isomers formed by transferof said hydrogen atom to a basic group or atom within the molecule.

Pharmaceutically acceptable salts of compounds of Formula I may beprepared by one or more of these methods:

-   -   (i) by reacting the compound of Formula I with the desired acid;    -   (ii) by reacting the compound of Formula I with the desired        base;    -   (iii) by removing an acid- or base-labile protecting group from        a suitable precursor of the compound of Formula I or by        ring-opening a suitable cyclic precursor, for example, a lactone        or lactam, using the desired acid; or    -   (iv) by converting one salt of the compound of Formula I to        another by reaction with an appropriate acid or by means of a        suitable ion exchange column.

All these reactions are typically carried out in solution. The salt, mayprecipitate from solution and be collected by filtration or may berecovered by evaporation of the solvent. The degree of ionization in thesalt may vary from completely ionized to almost non-ionized.

The term “solvate” is used herein to describe a molecular complexcomprising the compound of the invention and one or morepharmaceutically acceptable solvent molecules, for example, ethanol. Theterm ‘hydrate’ is employed when said solvent is water.

All references to compounds of formula I include references to salts,solvates, multi-component complexes and liquid crystals thereof.

The compounds of the invention include compounds of formula I ashereinbefore defined, including all polymorphs and crystal habitsthereof, prodrugs and isomers thereof (including optical, geometric andtautomeric isomers) and isotopically-labeled compounds of formula I.

In addition, although generally, with respect to the salts of thecompounds of the invention, pharmaceutically acceptable salts arepreferred, it should be noted that the invention in its broadest sensealso included non-pharmaceutically acceptable salts, which may forexample be used in the isolation and/or purification of the compounds ofthe invention. For example, salts formed with optically active acids orbases may be used to form diastereoisomeric salts that can facilitatethe separation of optically active isomers of the compounds of Formula Iabove.

The invention also generally covers all pharmaceutically acceptablepredrugs and prodrugs of the compounds of Formula I.

The term “prodrug” as used herein means the pharmacologically acceptablederivatives of compounds of formula I such as esters whose in vivobiotransformation product is the active drug. Prodrugs are characterizedby increased bio-availability and are reaily metabolized into the activecompounds in vivo.

The term “predrug”, as used herein, means any compound that will bemodified to form a drug species, wherein the modification may take placeeither inside or outside of the body, and either before or after thepredrug reaches the area of the body where administration of the drug isindicated.

The term “patient” refers to a warm-blooded animal, more preferably ahuman, who/which is awaiting or receiving medical care or is or will bethe object of a medical procedure.

The term “human” refers to suject of both genders and at any stage ofdevelopment (i.e. neonate, infant, juvenile, adolescent, adult).

The terms “treat”, “treating” and “treatment, as used herein, are meantto include alleviating or abrogating a condition or disease and/or itsattendant symptoms.

The terms “prevent”, “preventing” and “prevention”, as used herein,refer to a method of delaying or precluding the onset of a condition ordisease and/or its attendant symptoms, barring a patient from acquiringa condition or disease, or reducing a patient's risk of acquiring acondition or disease.

The term “therapeutically effective amount” (or more simply an“effective amount”) as used herein means the amount of active agent oractive ingredient (e. g. NK-3 antagonist) which is sufficient to achievethe desired therapeutic or prophylactic effect in the individual towhich it is administered.

The term “administration”, or a variant thereof (e.g., “administering”),means providing the active agent or active ingredient (e. g. a NK-3antagonist), alone or as part of a pharmaceutically acceptablecomposition, to the patient in whom/which the condition, symptom, ordisease is to be treated or prevented.

By “pharmaceutically acceptable” is meant that the ingredients of apharmaceutical composition are compatible with each other and notdeleterious to the patient thereof.

The term “antagonist” as used herein means a compound whichcompetitively or non-competitively binds to a receptor at the same siteas an agonist (for example, the endogenous ligand), but does notactivate an intracellular response initiated by an active form of thereceptor. An antagonist thereby inhibits the intracellular responseinduced by an agonist.

The term “sex hormone-dependent disease” as used herein means a diseasewhich is exacerbated by, or caused by, excessive, inappropriate orunregulated sex hormone production. Exemple of such diseases in meninclude but not limited to benign prostatic hyperplasia (BPH),metastatic prostatic carninoma, testicular cancer, breast cancer,androgen dependent acne, male pattern baldness. Exemple of such diseasesin women include but not limited to endometriosis, abnormal puberty,uterine fibrosis, hormone-dependent cancers (ovarian cancer, breastcancer), hyperandrogenism, hirsutism, virilization, polycystic ovarysyndrome (PCOS), HAIR-AN syndrome (hyperandrogenism, insulin resistanceand acanthosis nigricans), ovarian hyperthecosis (HAIR-AN withhyperplasia of luteinized theca cells in ovarian stroma), othermanifestations of high intraovarian androgen concentrations (e.g.follicular maturation arrest, atresia, anovulation, dysmenorrhea,dysfunctional uterine bleeding, infertility) and androgen-producingtumor (virilizing ovarian or adrenal tumor).

The term “Psychotic disorders” as used herein means a group of illnessesthat affect the mind. These illnesses alter a patient's ability to thinkclearly, make good judgments, respond emotionally, communicateeffectively, understand reality, and behave appropriately. When symptomsare severe, patient with psychotic disorders have difficulty staying intouch with reality and often are unable to meet the ordinary demands ofdaily life. Psychotic disorders include, and are not limited to,schizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition,substance-induced psychotic disorder or psychotic disorder not otherwisespecified (Diagnostic and Statistical Manual of Mental Disorders, Ed.4th, American Psychiatric Association, Washington, D.C. 1994).

The term “pharmaceutical vehicle” as used herein means a carrier orinert medium used as solvent or diluent in which the pharmaceuticallyactive agent is formulated and/or administered. Non-limiting examples ofpharmaceutical vehicles include creams, gels, lotions, solutions, andliposomes.

The present invention will be better understood with reference to thefollowing examples. These examples are intended to representative ofspecific embodiments of the invention, and are not intended as limitingthe scope of the invention.

Chemistry Examples

All temperatures are expressed in ° C. and all reactions were carriedout at room temperature (RT) unless otherwise stated.

Analytical thin layer chromatography (TLC) was used to monitorreactions, establish flash chromatography conditions and verify purityof intermediates or final products. TLC plates used were Merck TLCaluminium sheet silica gel 60 F₂₅₄. TLC plates were revealed usingultraviolet irradiation (wavelength=254 nm) at room temperature orbromocresol green spray reagent at 0.1% in propan-2-ol purchased fromVWR International upon heating at 160° C. or KMnO₄ revelator uponheating at 160° C. The KMnO₄ TLC revealing agent was prepared bydissolving 3 g of potassium permanganate, 20 g of sodium carbonate, 0.5g of sodium hydroxide in 100 mL of distilled water.

HPLC-MS spectra were obtained on Agilent LCMS using Electropsrayionization (ESI). The Agilent instrument includes an Autosampler 1200, abinary pump 1100, a 5 wave length detector 1100 and a 6100 Single Quad.The column used was an XBridge C18, 4.6×50 mm, 3.5 μm.

Eluent was a mixture of solution A (0.1% TFA in H₂O) and solution B(0.1% TFA in ACN). Gradient was applied at a flow rate of 2 mL min⁻¹ asfollows: gradient A: held the initial conditions of 5% solution B for 1min, increased linearly to 95% solution B in 4 min, held at 95% during 1min, returned to initial conditions in 0.5 min and maintained for 1 min;gradient B: held the initial conditions of 5% solution B for 1 min,increased linearly to 60% in 10 min, increased linearly to 95% in 0.5min, held at 95% during 3 min, returned to initial conditions in 0.5 minand maintained for 1 min.

Determination of ee was performed on an Agilent 1100 (binary pump and 5wavelengths detector) with manual or automatic (Autosampler 1100)injection. Columns used were CHIRALPAK IA CHIRALPAK IB or CHIRALPAK ICin isocratic mode. Mixtures of eluents were selected depending on theseparation obtained of enantiomers or diastereosiomers. Usual mixtureswere:

-   -   hexane and ethanol (0.1% DEA)    -   hexane and isoropanol (0.1% DEA)    -   hexane and ethyl acetate (0.1% DEA)    -   hexane and dichloromethane (0.1% DEA)    -   heptane and THF (0.1% DEA)

Preparative HPLC purifications were carried out on Fractionlynxinstrument, from Waters. This instrument consists of a FractionCollector, a 2767 Sample Manager, a pump control a module II, a 515 HPLCPump, a 2525 Binary Gradient Module, a Switching Valve, a 2996Photodiode Array Detector and a Micromass ZQ. The column used was aWaters Sunfire C18 Eluent was a mixture of solution A (0.1% TFA in H₂O)and solution B (0.1% TFA in ACN). The gradient was adapted depending onimpurities present in samples, to allow sufficient separation betweenimpurities and target compound.

Chiral preparative HPLC purification were performed on an Agilent 1100instrument (binary pump and 5 wavelengths detector) with manualinjection using a CHIRALPAK IA or a CHIRALPAK IB column in isocraticmode. Mixtures of eluents were selected depending on the separation ofenantiomers or diastereosiomers obtained with the analytical method.Usual mixtures were the same as those used for the determination of ee.

¹H and ¹³C NMR spectra were recorded on a Bruker Avance DRX 300 MHz.Chemical shifts are expressed in parts per million, (ppm, 6 units).Coupling constants are expressed in Hertz units (Hz). Splitting patternsdescribe apparent multiplicities and are described as s (singlet), d(doublet), t (triplet), q (quadruplet), m (multiplet), or br (broad).

Solvents, reagents and starting materials were purchased from well knownchemical suppliers such as for example Sigma Aldrich, Acros Organics,Fluorochem, Eurisotop, VWR International, Sopachem and Polymer labs andthe following abbreviations are used:

ACN: Acetonitrile, DCM: Dichloromethane, DMF: N,N-dimethylformamide,

EtOAc: Ethyl acetate,

EtOH: Ethanol, MeOH: Methanol,

IPA: isopropanol,RT: Room temperature,

Y: Yield, g: Gram(s), mg: Milligram(s), L: Liter(s), mL: Milliliter(s),μL: Microliter(s), mol: Mole(s),

mmol: Millimole(s),

h: Hour(s), mn or min: Minute(s),

TLC: Thin layer chromatography,MW: Molecular weight,

eq: Equivalent,

μW or μwave: Microwave,

THF: Tetrahydrofuran, Ac: Acetyl,

ee: Enantiomeric excess,tBu: tert-ButylP: UV purity at 254 nm or 215 nm determined by HPLC-MS,SPE: Solid phase extraction,rt: Retention time.DEA: diethylamine,HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tretramethyluroniumhexafluorophosphate,TFA: trifluoroacetic acid,DBU: 1,8-Diazabicyclo[5.4.0]undec-7-eneTMS: trimethylsilyl,CDI: carbonyldiimidazole,rm or RM: reaction mixture,dba: dibenzylideneacetone,X-Phos: 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl,THP: tetrahydropyran,Boc: tert-butoxycarbonyl,

DPPF: Diphenylphosphinoferrocene.

The intermediates and compounds disclosed hereunder were named usingChemDraw Ultra 12 purchased from CambridgeSoft (Cambridge, Mass., USA).

General Synthetic Scheme

Most compounds of the invention were synthesized using the methodologydescribed in scheme 1. The chiral compounds were obtained either bypurification using chiral HPLC, or by employing the appropriate chiralketopiperazine building block.

Ketopiperazine 1.1 was protected with a Boc group and converted toiminoether 1 by using Meerwein reagent (i.e., Et₃OBF₄). Ester 1.2 wassubsequently converted to acyl hydrazide 2 through its reaction withhydrazine, either in N-Boc-protected form (i.e. 1.2→2, condition a), orwithout protection (i.e. 1.2→2, condition b). Condensation reactionbetween the acyl hydrazide thus generated and the iminoetheraforementioned was conducted either under thermal reflux conditions, orby applying microwave irradiation. In case of reactions conducted usingmicrowave irradiation, the N-Boc deprotection occurred during thecondensation reaction, thus a deprotection step was not necessary tocarry out (i.e. 1+2→3 in Scheme 1). However, when condensation reactionwas carried out under thermal conditions, it was necessary to introducea deprotection step (i.e. 1+2→1.3→3). Acylation of the amine in thetriazolopiperazine intermediate 1.5, either through reaction with theappropriate acid chloride or through reaction with the appropriateactivated ester, i.e. conditions A and B respectively, afforded thefinal target structure. This synthetic approach was used for themajority of the compounds described in the present invention.

General Method A:

General Method A is the general procedure used for the synthesis of theiminoether intermediates 1 (cf. Scheme 1) and is detailed below usingthe example of tert-butyl 3-ethoxy-5,6-dihydropyrazine-1(2H)-carboxylate1a.

Step 1: Synthesis of tert-butyl 3-oxopiperazine-1-carboxylate 2.2

Boc₂O (10.9 g, 0.05 mol) was added in portions under stirring andcooling on an ice bath to a suspension of piperazin-2-one 2.1 (5 g, 0.05mol) in anhydrous dichloromethane (100 mL). The reaction mixture wasstirred at 20° C. overnight (evolution of gas was observed at thebeginning of the reaction), during which time a homogeneous solutionformed. The solvent was evaporated, and the solid residue wasvacuum-dried (10-15 mm Hg) at 40-50° C. to constant weight to give 2.2.Yield: 100 g (100%).

Step 2: Synthesis of tert-butyl5-ethoxy-3,6-dihydropyrazine-1(2H)-carboxylate 1a

Solid triethyloxonium tetrafluoroborate (2.3 g, 0.012 mol) was added inportions under stirring and cooling on an ice bath to a solution of 2.2(2 g, 0.01 mol) in anhydrous dichloromethane (20 mL). After the additionwas completed, the cooling was removed, and the reaction mixture wasstirred at room temperature overnight. Then a 20% K₂CO₃ aqueous solutionwas added in portions under cooling on an ice bath to the obtainedslightly muddy solution to obtain pH 8-9. The formed precipitate ofpotassium tetrafluoroborate was removed by filtration and washed onfilter with dichloromethane. The filtrate was placed into a separatoryfunnel, and the organic layer was separated. The aqueous layer wasextracted with dichloromethane (3×10 mL), and the combined organicextracts were washed with water (20 mL), dried over Na₂SO₄ andconcentrated on a rotary evaporator. Hexane was added to the residue,and the obtained mixture was left to stand in a refrigerator for ˜4 h.The formed precipitate was removed by filtration using a thin pad ofCelite, and the filtrate was evaporated. The obtained viscous yellowishoil was vacuum-dried (10-15 mm Hg) at 40-50° C. for ˜6 h to give titleintermediate 1a. Yield: 2.03 g (88%). ¹HNMR (CDCl₃): δ: 4.1 ppm (q, 2H),3.85 (s, 2H), 3.5 ppm (m, 1H), 3.35 ppm (t, 2H), 1.45 ppm (s, 9H), 1.3ppm (t, 3H).

Alternatively, general method A was carried out as follows:

Step 1: Synthesis of tert-butyl 3-oxopiperazine-1-carboxylate 2.2

To a solution of piperazin-2-one 2.1 (5.0 g, 33.2 mmol) in commercialanhydrous CH₂Cl₂ (100 mL) under N₂ at RT was added NEt₃ (5.1 mL, 35.5mmol). After 10 min stirring, the RM. was cooled down to 0° C. with anice bath and Boc₂O (8.33 g, 38.2 mmol) was added in one portion. TheRM.was then stirred at RT for 1 h. The mixture was diluted with 50 mL ofCH₂Cl₂ and washed with HCl 0.5M (30 mL), brine (30 mL), dried overmagnesium sulfate, filtered and concentrated to constant weightfurnishing 2.2 as a yellow oil. Yield: 7.1 g (100%). LCMS and ¹HNMR dataare consistent with those described above.

Step 2: Synthesis of tert-butyl5-ethoxy-3,6-dihydropyrazine-1(2H)-carboxylate 1a

To a pre-made solution of triethyloxonium tetrafluoroborate (2.3 g,0.012 mol) in anhydrous dichloromethane (20 mL) was added 2.2 (2 g, 0.01mol) at 0° C. After the addition was completed, the ice-bath wasremoved, and the reaction mixture was allowed to warm to roomtemperature and stirred for an additional hour (reaction progressmonitored by LC-MS). Upon completion of the reaction, a saturatedsolution of NaHCO₃ (500 mL) was slowly added to the reaction mixture andit was stirred for 5 min. The organic layer was separated and theaqueous layer was further extracted with dichloromethane. The combinedorganic layers were subsequently washed with brine, dried over MgSO₄,filtered and further dried in vacuo to obtain the title intermediate 1aas a viscous yellow oil. Yield: 2.03 g (88%). ¹HNMR (CDCl₃): δ: 4.1 ppm(q, 2H), 3.85 (s, 2H), 3.5 ppm (m, 1H), 3.35 ppm (t, 2H), 1.45 ppm (s,9H), 1.3 ppm (t, 3H).

The following intermediates were also prepared from the ad hoc reagentsusing General Method A:

-   intermediate 1b: (R)-tert-butyl    3-ethoxy-2-methyl-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1c: (S)-tert-butyl    3-ethoxy-2-methyl-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1d: tert-butyl    3-ethoxy-2-methyl-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1e: tert-butyl    3-ethoxy-2-(4-fluorophenyl)-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1f: tert-butyl    3-ethoxy-2-isopropyl-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1g: tert-butyl    3-ethoxy-2-(2-hydroxyethyl)-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1h: tert-butyl    3-ethoxy-2,2-dimethyl-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1i: tert-butyl    3-ethoxy-6-methyl-5,6-dihydropyrazine-1(2H)-carboxylate,-   intermediate 1j: tert-butyl 3-ethoxy-5-methyl-5,6-dihydropyrazine-1    (2H)-carboxylate.

General Method B:

General Method B is the general procedure used for the synthesis ofhydrazide intermediates 2 and is detailed below using the example ofquinoline-2-carbohydrazide 2a.

Step 1: Synthesis of methyl quinoline-2-carboxylate 3.2

To an ice-cooled solution of quinoline-2-carboxylic acid 3.1 (10 g,0.0578 mol) in 100 mL of absolute methanol was added dropwise thionylchloride (20 g, 0.173 mol). After the addition was completed, themixture was heated to reflux for 2 h. The solvent was then evaporated todryness under reduced pressure and treated with 100 mL of 10% aqueoussolution of K₂CO₃. The mixture was extracted with ethyl acetate;combined organic extracts were dried over sodium sulfate and evaporatedto dryness to afford of methyl quinoline-2-carboxylate. Yield: 10.1 g(93%).

Step 2: Synthesis of quinoline-2-carbohydrazide 2a

Methyl quinoline-2-carboxylate 3.2 (10.1 g, 0.054 mol) was dissolved in50 mL of ethanol and hydrazine hydrate (8.1 g, 0.16 mol) was added. Themixture was heated to reflux for 1 h and cooled down to RT at whichpoint a precipitate formed. The mixture was concentrated toapproximately 1/3 of the volume and the precipitate was filtered off,washed with small volumes of ethanol to afford intermediate 2a solvatedby ½ equivalent of ethanol. Yield 10 g (99%). ¹HNMR (DMSO-d⁶): δ: 9.95ppm (s, 1H), 8.55 (d, 1H), 8.1 ppm (d, 2H), 8.05 ppm (d, 1H), 8.85 ppm(t, 1H), 7.65 ppm (t, 1H), 4.6 ppm (s, 2H), 4.3 ppm (t, 0.5H), 4.4 ppm(q, 1H), 1.05 ppm (q, 1.5H).

In one embodiment 5 to 20 equivalents of hydrazine hydrate was used tocarry out this reaction.

The following intermediates were also prepared from the ad hoc reagentsusing General Method B:

-   intermediate 2b: 6-chloropicolinylhydrazide,-   intermediate 2c: 6-methylpicolinylhydrazide,-   intermediate 2d: isoquinoline-3-carbohydrazide,-   intermediate 2e: 8-fluoroquinoline-2-carbohydrazide,-   intermediate 2f: 8-chloroquinoline-2-carbohydrazide,-   intermediate 2g:    2-(4-(trifluoromethyl)phenyl)thiazole-4-carbohydrazide,-   intermediate 2h: 6-phenylpicolinohydrazide,-   intermediate 2i:    4,5,6,7-tetrahydrobenzo[d]thiazole-2-carbohydrazide,-   intermediate 2j: benzo[d]thiazole-2-carbohydrazide,-   intermediate 2k: 2-(2,4-difluorophenyl)thiazole-4-carbohydrazide,-   intermediate 2l: 2-(4-chlorophenyl)thiazole-4-carbohydrazide,-   intermediate 2m: 2-(4-fluorophenyl)thiazole-4-carbohydrazide,-   intermediate 2n: 2-(piperidin-1-yl)thiazole-4-carbohydrazide,-   intermediate 2o:    2-(4-phenylpiperazin-1-yl)thiazole-4-carbohydrazide,-   intermediate 2p: 2-(2,4-dichlorophenyl)thiazole-4-carbohydrazide,-   intermediate 2q: 2-(3,5-dichlorophenyl)thiazole-4-carbohydrazide,-   intermediate 2r: 6-(pyrrolidin-1-yl)picolinohydrazide,-   intermediate 2s: 6-morpholinopicolinohydrazide,-   intermediate 2t: 6-(trifluoromethyl)picolinohydrazide,-   intermediate 2u: 2-(3,4-dimethoxyphenyl)thiazole-4-carbohydrazide,-   intermediate 2v: 2-(3-chlorophenyl)thiazole-4-carbohydrazide,-   intermediate 2w: 2-phenyloxazole-4-carbohydrazide,-   intermediate 2x: 2-(2-chlorophenyl)thiazole-4-carbohydrazide,-   intermediate 2y: 5-methyl-2-phenylthiazole-4-carbohydrazide,-   intermediate 2z: 3-phenyl-1,2,4-oxadiazole-5-carbohydrazide,-   intermediate 2a1: 5-phenyl-1,2,4-oxadiazole-3-carbohydrazide,-   intermediate 2b1:    3-(4-fluorophenyl)-1,2,4-oxadiazole-5-carbohydrazide,-   intermediate 2c1    3-(2,4-difluorophenyl)-1,2,4-oxadiazole-5-carbohydrazide, was    synthesized-   from intermediate 5a obtained using General Method E,-   intermediate 2d1: 5-phenyl-1H-1,2,4-triazole-3-carbohydrazide, was    synthesized from methyl 5-phenyl-1H-1,2,4-triazole-3-carboxylate    whose preparation is disclosed in J. Med. Chem. 1995, 38, 2196,-   intermediate 2e1:    2-((4,5-dichloro-1H-imidazol-1-yl)methyl)thiazole-4-carbohydrazide,-   intermediate 2f1: 2-(4-chlorobenzyl)thiazole-4-carbohydrazide-   intermediate 2g1: 2-(p-tolyl)thiazole-4-carbohydrazide,-   intermediate 2h1: 2-(2-methoxyphenyl)thiazole-4-carbohydrazide,-   intermediate 2i1: 2-(3-fluorophenyl)thiazole-4-carbohydrazide,-   intermediate 2j1:    3-(4-fluorophenyl)-1,2,4-oxadiazole-5-carbohydrazide,-   intermediate 2k1: 3-phenyl-1,2,4-thiadiazole-5-carbohydrazide,-   intermediate 2l1: 2-(4-bromophenyl)thiazole-4-carbohydrazide,-   intermediate 2m1: 2-(pyridin-4-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 6b obtained using the General Method    F,-   intermediate 2n1: 2-(quinolin-2-yl)thiazole-4-carbohydrazide,-   intermediate 2o1: 1-methyl-3-phenyl-1H-pyrazole-5-carbohydrazide,-   intermediate 2p1:    2-(4-(dimethylamino)phenyl)thiazole-4-carbohydrazide,-   intermediate 2q1: 1-methyl-5-phenyl-1H-pyrazole-3-carbohydrazide,-   intermediate 2r1: 2-(pyridin-2-yl)thiazole-4-carbohydrazide,-   intermediate 2s1: 2-(pyrimidin-2-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 6d obtained using General Method F-   intermediate 2t1: 2-(pyrazin-2-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 6e obtained using General Method F,-   intermediate 2u1: 2-(4-morpholinophenyl)thiazole-4-carbohydrazide,    was synthesized from intermediate 7b obtained using General Method    G,-   intermediate 2v1:    2-(4-(4-methylpiperazin-1-yl)phenyl)thiazole-4-carbohydrazide,-   intermediate 2w1:    2-(4-(piperidin-1-yl)phenyl)thiazole-4-carbohydrazide, was    synthesized from intermediate 7c obtained using General Method G,-   intermediate 2x1:    2-(4-(pyrrolidin-1-yl)phenyl)thiazole-4-carbohydrazide, was    synthesized from intermediate 7d obtained using General Method G,-   intermediate 2y1: 2-(piperidin-1-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 7e obtained using General Method G,-   intermediate 2z1: 2-(pyrrolidin-1-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 7f obtained using General Method G,-   intermediate 2a2:    2-(4-methylpiperazin-1-yl)thiazole-4-carbohydrazide, was synthesized    from intermediate 7g obtained using General Method G,-   intermediate 2b2: 1-methyl-2-phenyl-1H-imidazole-4-carbohydrazide,-   intermediate 2c2:    1-(2-methoxyethyl)-3-phenyl-1H-pyrazole-5-carbohydrazide, was    synthesized from intermediate 8a obtained using General Method H,-   intermediate 2d2: 2-isobutylthiazole-4-carbohydrazide, was    synthesized from ethyl 2-isobutylthiazole-4-carboxylate, which was    obtained from 3-methylbutanethioamide using the methodology reported    by Ciufolini, et al. in Journal of Organic Chemistry, 1997, vol. 62,    issue 12, p. 3804-3805,-   intermediate 2e2:    2-(2-(2-methoxyethyl)morpholino)thiazole-4-carbohydrazide, was    synthesized from intermediate 7h obtained using General Method G,-   intermediate 2f2:    2-(4,4-difluoropiperidin-1-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 7i obtained using General Method G,-   intermediate 2g2:    2-(2,5-dimethylmorpholino)thiazole-4-carbohydrazide, was synthesized    from intermediate 7i obtained using General Method G,-   intermediate 2h2: 2-(2-hydroxyphenyl)thiazole-4-carbohydrazide, was    synthesized from ethyl 2-(2-hydroxyphenyl)thiazole-4-carboxylate,    which was obtained from 2-hydroxybenzothioamide using the    methodology reported by Ciufolini, et al. in Journal of Organic    Chemistry, 1997, vol. 62, issue 12, p. 3804-3805,-   intermediate 2i2:    2-(2,6-dimethylmorpholino)thiazole-4-carbohydrazide, was synthesized    from intermediate 7k obtained using General Method G,-   intermediate 2j2:    2-(2,2-dimethylmorpholino)thiazole-4-carbohydrazide, was synthesized    from intermediate 71 obtained using General Method G,-   intermediate 2k2: 3-phenyl-1H-pyrazole-5-carbohydrazide,-   intermediate 212: 2-(2-methylmorpholino)thiazole-4-carbohydrazide,    was synthesized from intermediate 7m obtained using General Method    G,-   intermediate 2m2:    2-(4,4-dimethylpiperidin-1-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 7n obtained using General Method G,-   intermediate 2n2: 5-methylthiazole-4-carbohydrazide,-   intermediate 2o2:    2-(2-(methoxymethyl)piperidin-1-yl)thiazole-4-carbohydrazide, was    synthesized from intermediate 7o obtained using General Method G,-   intermediate 2p2: 2-(2-bromophenyl)thiazole-4-carbohydrazide, was    synthesized from ethyl 2-(2-bromophenyl)thiazole-4-carboxylate,    which was obtained from 2-bromobenzothioamide using the methodology    reported by Ciufolini, et al. in Journal of Organic Chemistry, 1997,    vol. 62, issue 12, p. 3804-3805,-   intermediate 2q2: 2-(3-bromophenyl)thiazole-4-carbohydrazide, was    synthesized from ethyl 2-(3-bromophenyl)thiazole-4-carboxylate,    which was obtained from 3-bromobenzothioamide using the methodology    reported by Ciufolini, et al. in Journal of Organic Chemistry, 1997,    vol. 62, issue 12, p. 3804-3805,

General Method C:

General Method C is the general procedure used for the synthesis oftriazolopiperazine intermediates 3 and is detailed below with thesynthesis of(R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazolehydrochloride 3a.

Step 1: Synthesis of (R)-tert-butyl8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate4.2

To a solution of hydrazide 2-phenylthiazole-4-carbohydrazide 4.1 (100mg, 0.4 mmol) in ethanol (7 mL) was added (2R)-tert-butyl3-ethoxy-2-methyl-5,6-dihydropyrazine-1(2H)-carboxylate 1b (75 mg, 0.34mmol). To this reaction mixture was applied microwave radiation (110°C., 220 psi) for 25 h. The solvent was then evaporated to dryness andthe residue was purified on silica gel using CH₂Cl₂-Ethyl acetate(5:1→5:2+MeOH from 1% to 5%). Yield: 50 mg of 4.2+40 mg of de-Bocproduct 3a. Combined yield: 76%. %. LCMS: P=96%, rt=1.86 mn, m/z=398,298.

Step 2: Synthesis of(R)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazolehydrochloride 3a

Compound 4.2 (50 mg, 0.125 mmol) obtained in the previous step wasdissolved in isopropyl alcohol (10 mL) to which was added 0.3 mL of HCl4M in dioxane. The mixture was stirred at 50° C. overnight. Aftercooling down to RT, 10 mL of diethyl ether was added. The precipitatewas filtered to afford title intermediate. Yield: 42 mg, 99%. LCMS:P=100%, rt=1.08 mn, m/z=298. ¹H NMR (DMSO-d⁶): δ: 8.3 ppm (s, 1H), 8.05ppm (m, 2H), 7.55 ppm (m, 3H), 4.5 ppm (m, 1H), 4.25-4.05 ppm (m, 2H),3.3 ppm (m, 1H), 2.95-3.1 ppm (m, 1H), 2.8 ppm (br s, 1H), 1.95 ppm (d,3H).

Variant of General Method C is detailed below using the example of2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3q1.

Step 1: Synthesis of tert-butyl3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate4

To a solution of hydrazide 2m (1.65 g, 6.95 mmol) in anhydrous ethanol(15 mL, ˜0.5M) was added iminoether Id (1.69 g, 6.95 mmol) in oneportion. The reaction mixture was then stirred under reflux. After 45 h(nearly complete conversion by LC-MS), the solvent was evaporated todryness and the residue was purified on silica gel using a CH₂Cl₂/MeOHmixture (0% to 4% MeOH) as eluent, furnishing 4′ as a yellow solid.Yield: 2.1 g (73%). LCMS: P=92%, rt=4.4 mn, m/z=416. ¹HNMR (CDCl₃): δ:8.11 ppm (s, 1H), 7.97 ppm (t, 2H), 7.20 ppm (t, 2H), 4.75 (m, 1H), 4.52(m, 1H), 4.23 (dt, 1H), 4.17 (m, 1H), 3.48 (dt, 1H), 1.64 ppm (d, 3H),1.51 ppm (s, 9H).

Step 2 Synthesis of2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole3q1

To a solution of Boc-triazolo-piperazine 4′ (2.17 g, 5.22 mmol) iniso-propanol (150 mL) was added HCl 4M solution in 1,4-dioxane (26.1 mL,104 mmol) in one portion. The reaction mixture was stirred at 60° C. andthe reaction progress was monitored by LC-MS. After 1 h (completeconversion by LC-MS), the reaction mixture was allowed to cool to roomtemperature and then further cooled to 0° C. with an ice bath.Thereupon, 150 mL of Et₂O was added. After 15 min stirring, theprecipitate was filtered off and dried in vacuo to afford 3q1 as anoff-white solid. Yield: 1.313 g (72%). LCMS: P=98%, rt=3.3 mn, m/z=316.¹HNMR (CD₃OD): δ: 8.57 ppm (s, 1H), 8.15 ppm (t, 2H), 7.30 ppm (t, 2H),5.22 (m, 1H), 5.08 (q, 1H), 4.13 (m, 1H), 3.77 (m, 1H), 3.12 (m, 1H),1.94 ppm (d, 3H).

As noted in Scheme 4′ above, an alternative procedure to thermal refluxto effect the condensation step to form the triazolopiperazineintermediate entailed use of microwave irradiation. Such reactions wererun in anhydrous ethanol and the following conditions were typicallyapplied (CEM Discover): 300 W μwave (143° C.) with air-cooling.

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method C:

-   intermediate 3b:    3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3c:    4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine    dihydrochloride salt,-   intermediate 3d:    3-(5-chloropyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3e:    3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3f:    8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3g:    3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)isoquinoline    hydrochloride salt,-   intermediate 3h:    2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)quinoline    hydrochloride salt,-   intermediate 3i:    8-fluoro-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)quinoline    hydrochloride salt,-   intermediate 3j:    8-chloro-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)quinoline    hydrochloride salt,-   intermediate 3k:    4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(4-(trifluoromethyl)phenyl)thiazole    hydrochloride salt,-   intermediate 3l:    3-(6-phenylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3m:    2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-4,5,6,7-tetrahydrobenzo[d]thiazole    hydrochloride salt,-   intermediate 3n:    2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzo[d]thiazole    hydrochloride salt,-   intermediate 3o:    2-phenyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3p:    4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(3-(trifluoromethyl)phenyl)thiazole    hydrochloride salt,-   intermediate 3q:    2-(2,4-difluorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3r:    2-(2,3-dichlorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3s:    2-(4-chlorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3t:    2-(4-fluorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3u:    2-(piperidin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3v:    2-(4-phenylpiperazin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3w:    2-(2,4-dichlorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3x:    2-(3,5-dichlorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3y:    3-(6-(pyrrolidin-1-yl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3z:    4-(6-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)pyridin-2-yl)morpholine    dihydrochloride salt,-   intermediate 3a1:    3-(6-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3b1:    2-(3,4-dimethoxyphenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3c1:    4-(8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole    hydrochloride salt,-   intermediate 3d1:    2-(3-chlorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3e1:    4-(8-isopropyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole    hydrochloride salt,-   intermediate 3f1:    (R)-8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3g1:    4-(4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine    dihydrochloride salt,-   intermediate 3h1:    2-phenyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)oxazole    hydrochloride salt,-   intermediate 3i1:    4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenyloxazole,-   intermediate 3j1:    2-(3-(2-phenylthiazol-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)ethanol    hydrochloride salt,-   intermediate 3k1:    4-phenyl-2-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3l1:    2-(2-chlorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3m1:    4-(8,8-dimethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole    hydrochloride salt,-   intermediate 3n1:    2-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)quinoline    hydrochloride salt,-   intermediate 3o1:    4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole    hydrochloride salt,-   intermediate 3p1:    (R)-2-(4-chlorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3q1:    2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3r1:    (R)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3s1:    5-methyl-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-phenylthiazole    hydrochloride salt,-   intermediate 3t1:    2-(2-chlorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3u1:    2-(2,4-difluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3v1:    5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-3-phenyl-1,2,4-oxadiazole    hydrochloride salt,-   intermediate 3w1:    2-(4-fluorophenyl)-4-(6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3x1:    2-(4-fluorophenyl)-4-(5-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3y1:    (S)-8-methyl-3-(pyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine,-   intermediate 3z1:    (S)-2-(4-fluorophenyl)-4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,-   intermediate 3a2:    (S)-4-(4-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine,-   intermediate 3b2:    5-phenyl-3-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole    hydrochloride salt,-   intermediate 3c2:    3-phenyl-5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole    hydrochloride salt,-   intermediate 3d2    3-(4-fluorophenyl)-5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole    hydrochloride salt,-   intermediate 3e2:    3-(2,4-difluorophenyl)-5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole    hydrochloride salt,-   intermediate 3f2:    3-(5-phenyl-1H-1,2,4-triazol-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    hydrochloride salt,-   intermediate 3g2:    2-(2-fluorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3h2:    2-((4,5-dichloro-1H-imidazol-1-yl)methyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3i2:    2-(4-chlorobenzyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3j2:    4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(p-tolyl)thiazole    hydrochloride salt,-   intermediate 3k2:    4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-2-(thiophen-2-yl)thiazole    hydrochloride salt,-   intermediate 3l2:    2-(((4-chlorophenyl)sulfonyl)methyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3m2:    2-(2-methoxyphenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3n2:    2-(3-fluorophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3o2:    2-isopropyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3p2:    3-(4-fluorophenyl)-5-(8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-oxadiazole    hydrochloride salt,-   intermediate 3q2:    3-phenyl-5-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1,2,4-thiadiazole    hydrochloride salt,-   intermediate 3r2:    2-(4-bromophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3s2:    2-(pyridin-4-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3t2:    2-(quinolin-2-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3u2:    3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    hydrochloride salt,-   intermediate 3v2:    N,N-dimethyl-4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)aniline    dihydrochloride salt,-   intermediate 3w2:    3-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    hydrochloride salt,-   intermediate 3y2:    2-(pyridin-2-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3z2:    2-(pyrimidin-2-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3a3:    2-(pyrazin-2-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3b3:    4-(4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenyl)morpholine    hydrochloride salt,-   intermediate 3c3:    2-(4-(4-methylpiperazin-1-yl)phenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3d3:    2-(4-(piperidin-1-yl)phenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3e3:    2-(4-(pyrrolidin-1-yl)phenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3f3:    2-(piperidin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3g3:    2-(pyrrolidin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3h3:    2-(4-methylpiperazin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    dihydrochloride salt,-   intermediate 3i3:    3-(1-methyl-2-phenyl-1H-imidazol-4-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3j3:    3-(1-(2-methoxyethyl)-3-phenyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    hydrochloride salt,-   intermediate 3k3:    2-isobutyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3l3:    2-(2-methoxyethyl)-4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine    hydrochloride salt,-   intermediate 3m3:    2-(4,4-difluoropiperidin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3n3:    2,5-dimethyl-4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine    hydrochloride salt,-   Intermediate 303:    2-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenol-   hydrochloride salt,-   intermediate 3p3:    2,6-dimethyl-4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine    hydrochloride salt,-   intermediate 3q3:    2,2-dimethyl-4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine    hydrochloride salt,-   intermediate 3r3:    3-(3-phenyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3s3:    2-methyl-4-(4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)morpholine    hydrochloride salt,-   intermediate 3t3:    2-(4,4-dimethylpiperidin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3u3    5-methyl-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3v3    2-(2-(methoxymethyl)piperidin-1-yl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole    hydrochloride salt,-   intermediate 3w3:    8-methyl-3-(6-methylpyridin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine    dihydrochloride salt,-   intermediate 3x3:    2-(2-bromophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,-   intermediate 3y3:    2-(3-bromophenyl)-4-(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazole,

General Method D:

General Method D is the general procedure used for the synthesis of3-phenyl-pyrazole-5-carboxylic acid intermediates 4 and is exemplifiedbelow using the synthesis of3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid 4a and5-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid 4b.

Step 1: Synthesis of ethyl 4-(3,4-dichlorophenyl)-2,4-dioxobutanoate 5.2

To a solution of t-BuOK (0.05 mol, 5.6 g) in benzene (200 mL) was addeddropwise a benzene (50 mL) solution of 3,4-dichloroacetophenone 5.1(0.05 mol, 9.45 g) and diethyloxalate (0.055 mol, 8.1 g). The resultantmixture was stirred for 8 h at room temperature, then 10% aqueous HClsolution (100 mL) was added to the mixture. The organic layer wasseparated and washed with brine, dried over sodium sulfate andconcentrated in vacuo. The crude product was purified by columnchromatography using dichloromethane as eluent to yield the titlecompound. Yield: 7.5 g (52%).

Step 2: synthesis of ethyl3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-5-carboxylate 5.3 and ethyl5-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylate 5.4

To a solution of compound 5.2 (0.035 mol, 10.2 g) in ethanol (100 mL)was added monomethyl hydrazine (0.0353 mol, 1.63 g) and the resultantmixture was refluxed for 2 h, and subsequently stirred overnight at RT.The mixture was then evaporated to dryness and the thus obtained crudeproduct was subjected to column chromatography (eluent: ethylacetate/hexane 2:3). This afforded 3.68 g of compound 5.3 (R_(f)=0.8)and 3.28 g of compound 5.4 (R_(f)=0.6). The structure assignment of thethus obtained regioisomers was accomplished on the basis of NOE in2D-NOESY spectra and ¹H-¹³C cross-coupling constants in 2D-H-13C-HMBCspectra between N-methyl protons and quaternary carbons in the pyrazolerings.

Step 3: synthesis of3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid 4a and5-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acidhydrochloride salt 4b Synthesis of3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-5-carboxylate 4a

Compound 5.3 (0.0123 mol, 3.68 g) and sodium hydroxide (2 g) weredissolved in water-ethanol (1:1 v/v, 300 mL) solution. The mixture wasrefluxed for 3 h and then most of the ethanol was evaporated. The pH ofthe thus obtained mixture was adjusted to pH 3 by addition of 10% HClwhereupon a precipitate formed, which was filtered, washed with waterand air dried to afford compound 5.5. Yield: 3.05 g (91.6%). LCMS:P=97.5%, rt=1.86 mn, m/z=271. ¹HNMR (DMSO-d⁶): δ: 13.5 ppm (br s, 1H),8.05 ppm (s, 1H), 7.8 ppm (d, 1H), 7.6 ppm (d, 1H), 7.4 ppm (s, 1H),4.15 ppm (s, 3H).

Synthesis of 5-(3,4-dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylate4b

Compound 5.4 (10.08 mmol, 3.24 g) was refluxed in a mixture of conc. HCl50 mL/water 75 mL/dioxane 125 mL for 3 h. The volatiles were evaporateduntil the formation of a precipitate, which was filtered, washed withwater and air dried to afford product 5.6 as HCl salt. Yield: 2.79 g(90%). LCMS: P=95%, rt=1.67 mn, m/z=271. 1H NMR (DMSO-d⁶): δ: 7.9 ppm(s, 1H), 7.75 ppm (d, 1H), 7.6 ppm (d, 1H), 6.95 ppm (s, 1H), 3.9 ppm(s, 3H).

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method D:

-   Intermediate 4c: 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid,-   Intermediate 4d: 3-(3,4-dichlorophenyl)-1H-pyrazole-5-carboxylic    acid,-   Intermediate 4e: 3-(2,4-dichlorophenyl)-1H-pyrazole-5-carboxylic    acid,-   Intermediate 4f:    3-(4-trifluoromethylphenyl)-1H-pyrazole-5-carboxylic acid,-   Intermediate 4g: 3-(4-phenoxyphenyl)-1H-pyrazole-5-carboxylic acid,-   Intermediate 4h:    3-(4-chlorophenyl)-1-methyl-1H-pyrazole-5-carboxylic acid,-   Intermediate 4i:    5-(4-chlorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid.

General Method E:

General Method E is the general procedure used for the synthesis ofethyl 3-phenyl-1,2,4-oxadiazol-5-carboxylate intermediates 1.2 and isexemplified below with the synthesis of ethyl3-(2,4-difluorophenyl)-1,2,4-oxadiazole-5-carboxylate 5a.

Step 1: Synthesis of 2,4-difluoro-N′-hydroxybenzimidamide 5.2

To a solution of 2,4-difluorobenzonitrile 5.1 (1 g, 7.2 mmol) andhydroxylamine hydrochloride (1 g, 14.4 mmol) in commercial dry EtOH (5mL) under N₂ was added NEt₃ (2 mL, 14.4 mmol) dropwise over 2 min at RT.The mixture was stirred under reflux overnight. The mixture was thenallowed to cool down to RT and concentrated. The white solid obtainedwas used crude in the next step. Yield: 3.52 g (quantitative). LCMS:P=33%, rt=0.84 mn, m/z=173.

Step 2: Synthesis of ethyl3-(2,4-difluorophenyl)-1,2,4-oxadiazole-5-carboxylate 5a

To a solution of 2,4-difluoro-N′-hydroxybenzimidamide 5.2 (3.52 g, 33%purity, max. 7.2 mmol) and pyridine (2.32 mL, 28.7 mmol) in anhydrousCH₂Cl₂ under N₂ was added ethyl chlorooxoacetate (1.27 g, 9.32 mmol)dropwise over 5 min at RT. The mixture was stirred under reflux. After 1h30, the r×n mixt. was concentrated and purified on silica gel usingCH₂Cl₂, furnishing 1.414 g of title product 5a as colorless oil. Yield:1.414 g (78%). LCMS: P=94%, rt=4.21 mn, m/z=255, 277 (M+Na).

General Method F:

General Method E is the general procedure used for the synthesis ofmethyl 2-pyridyl-thiazol-4-carboxylate intermediates 1.2 and isexemplified below with the synthesis of methyl2-(pyridin-2-yl)thiazole-4-carboxylate 6a.

Step 1: Synthesis of tert-butyl thiazole-4-carboxylate 7.2

To a solution of thiazole-4-carboxylic acid 7.1 (1 g, 7.2 mmol) andcarbonyldiimidazole (6.3 g, 38.7 mmol) in commercial dry DMF (50 mL)under N₂ was stirred at 50° C. for 20 min. Tert-butanol (8.6 g, 116.0mmol) and DBU (5.8 mL, 38.7 mmol) were then successively added at onceand the reaction was warmed at 60° C. for 48 h. The RM was then allowedto cool down to RT and the pH was adjusted to 4 with a solution of HCl(2M, ˜80 mL). The mixture was diluted with water (250 mL) and extractedwith Et₂O (3×100 mL). The combined org. layers were washed with brine(250 mL), dried over MgSO₄, concentrated and purified on silica gelusing DCM to afford title product as yellowish oil (47%). Yield: 3.37 g(47%). LCMS: P=98%, rt=3.65 mn, m/z=186.

Step 2: Synthesis of tert-butyl 2-(pyridin-2-yl)thiazole-4-carboxylate7.3

To a solution of tert-butyl thiazole-4-carboxylate 7.2 (256 mg, 1.62mmol), anhydrous cesium carbonate (1 g, 3.24 mmol) and 2-bromo-pyridine(300 mg, 1.62 mmol) sequentially added in commercial anhydrous DMF (6mL) at RT under N₂ was added Pd(OAc)₂ (18 mg, 0.08 mmol) and(2-biphenyl)dicyclohexyl phosphine (57 mg, 0.16 mmol). The RM was heatedat 110° C. overnight. The RM was then allowed to cool down to RT,filtered on Celite pad and concentrated. The residue was purified onsilica gel using cyclohexane/EtOAc (5% to 20% of EtOAc), furnishing 7.3as yellow oil. Yield: 340 mg (80%). LCMS: P=96%, rt=4.28 mn, m/z=263.

Step 3: Synthesis of 2-(pyridin-2-yl)thiazole-4-carboxylic acid 7.4

To a solution of tert-butyl 2-(pyridin-2-yl)thiazole-4-carboxylate 7.3(340 mg, 1.3 mmol) in commercial anhydrous CH₂Cl₂ (5 mL) at RT was addedTFA (0.93 mL, 13 mmol) under N₂. The mixture was stirred at RTovernight. The mixture was diluted with CH₂Cl₂ (25 mL), washed with anaqueous solution of NaHSO₃ 10% (5×25 mL), brine (25 mL) and then water(25 mL). The organic layer was dried over MgSO₄ and evaporated to affordtitle product as a yellow oil. Yield: 250 mg (94%). LCMS: P=93%, rt=3.03mn, m/z=207.

Step 4: Synthesis of methyl 2-(pyridin-2-yl)thiazole-4-carboxylate 6a

To a solution of 2-(pyridin-2-yl)thiazole-4-carboxylic acid 7.4 (500 mg,2.425 mmol) in commercial anhydrous methanol (10 mL) was added TMS-C1(0.77 mL, 6.06 mmol) at once. The RM was heated to 50° C. overnight. TheRM. was concentrated under reduced pressure and the residue was usedcrude in next step. Yield: 649 mg (quantitative). LCMS: P=94%, rt=4.07mn, m/z=221.

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method F:

-   intermediate 6b: methyl 2-(pyridin-4-yl)thiazole-4-carboxylate,-   intermediate 6c: methyl 2-(quinolin-2-yl)thiazole-4-carboxylate,-   intermediate 6d: methyl 2-(pyrimidin-2-yl)thiazole-4-carboxylate,-   intermediate 6e: methyl 2-(pyrazin-2-yl)thiazole-4-carboxylate.

General Method G:

General Method G is the general procedure used for the synthesis ofmethyl 2-(4-heterocyclylphenyl)thiazole-4-carboxylate intermediates 1.2and is exemplified below with the synthesis of methyl2-(4-(4-methylpiperazin-1-yl)phenyl)thiazole-4-carboxylate 7a.

In a tube previously dried in a 113° C.-heated oven overnight wereintroduced successively 2-(4-bromophenyl)thiazole-4-carboxylate 8.1 (500mg, 1.6 mmol), 1-methylpiperazine (0.21 mL, 1.9 mmol) and anhydrouscesium carbonate (1.04 g, 3.0 mmol) under N₂. Commercial anhydroustoluene (10 mL) was then added and RM was degassed (argon bubbling for˜5 min). Pd₂(dba)₃ (73 mg, 0.08 mmol) and X-Phos (76 mg, 0.16 mmol) werequickly added successively and the mixture was heated under refluxovernight. The reaction mixture was then allowed to cool down to RT andEtOAc (50 mL) was added. This mixture was washed with brine (30 mL) andthe aqueous layer was further extracted twice with EtOAc (30 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedunder reduced pressure. The residue was purified on silica gel usingCH₂Cl₂/MeOH (2% of MeOH) to afford title product as a yellow solid.Yield: 374 mg (71%). LCMS: P=92%, rt=3.31 mn, m/z=332.

This General Method was also applied to the synthesis of methyl2-heterocyclylthiazole-4-carboxylate intermediates, starting from methyl2-bromothiazole-4-carboxylate.

The following intermediates were also prepared from the ad hoc reagentsand intermediates using General Method G

-   intermediate 7b: methyl    2-(4-morpholinophenyl)thiazole-4-carboxylate,-   intermediate 7c: methyl    2-(4-(piperidin-1-yl)phenyl)thiazole-4-carboxylate,-   intermediate 7d: methyl    2-(4-(pyrrolidin-1-yl)phenyl)thiazole-4-carboxylate,-   intermediate 7e: methyl 2-(piperidin-1-yl)thiazole-4-carboxylate,-   intermediate 7f: methyl 2-(pyrrolidin-1-yl)thiazole-4-carboxylate,-   intermediate 7g: methyl    2-(4-methylpiperazin-1-yl)thiazole-4-carboxylate,-   intermediate 7h: methyl    2-(2-(2-methoxyethyl)morpholino)thiazole-4-carboxylate,-   intermediate 7i: methyl    2-(4,4-difluoropiperidin-1-yl)thiazole-4-carboxylate,-   intermediate 7j: methyl    2-(2,5-dimethylmorpholino)thiazole-4-carboxylate,-   intermediate 7k: methyl    2-(2,6-dimethylmorpholino)thiazole-4-carboxylate,-   intermediate 7l: methyl    2-(2,2-dimethylmorpholino)thiazole-4-carboxylate,-   intermediate 7m: methyl    2-(2-methylmorpholino)thiazole-4-carboxylate,-   intermediate 7n: methyl    2-(4,4-dimethylpiperidin-1-yl)thiazole-4-carboxylate,-   intermediate 7o: methyl    2-(2-(methoxymethyl)piperidin-1-yl)thiazole-4-carboxylate,

General Method H:

General Method H is the general procedure used for the synthesis ofmethyl 3-phenylpyrazole-5-carboxylate and methyl5-phenylpyrazole-3-carboxylate intermediates 1.2 and is exemplifiedbelow with the synthesis of methyl1-(2-methoxyethyl)-3-phenyl-1H-pyrazole-5-carboxylate 8a and methyl1-(2-methoxyethyl)-5-phenyl-1H-pyrazole-3-carboxylate 8b.

To a solution of methyl 3-phenyl-1H-pyrazole-5-carboxylate 9.1 (250 mg,1.24 mmol) in commercial anhydrous acetone (30 mL) at RT under N₂ wasadded cesium carbonate at once (806 mg, 2.47 mmol). After 10 minstirring, 2-bromoethyl-methylether (258 mg, 1.85 mmol) was added atonce. The reaction mixture was refluxed for 2 h and then allowed to cooldown and concentrated, diluted with CH₂Cl₂ (50 mL) and washed with water(50 mL). The organic layer was then dried over MgSO₄, filtered andevaporated to dryness. The residue was purified on silica gel usingCH₂Cl₂/MeOH (1% of MeOH) to afford a mixture of 8a alongside with 8b(˜10%) as a pale yellow oil. Yield: 359 mg (71%). LCMS: P=100%, ratio8a/8b=9/1, 8a: rt=4.41 mn, m/z=261; 8b. rt=3.95 mn, m/z=261.

Additional Synthetic Schemes

The synthesis of compounds no 283, 289, 290, 291, 292 was carried outaccording to scheme 10

Thioamide 10.1 is condensed with ethyl 3-bromo-2-oxopropanoate to yieldthiazole ester intermediate 10.2 which was further converted tothiazolylhydrazide 10.3. Condensation of 10.3 with iminoether 1 providedaniline 10.4 which could be further converted to N-methylsulfonylaniline10.5a or dimethylaniline 10.5b. Boc deprotection followed acylationyielded compounds 10.7a and 10.7b. Di-acylated product 10.7a could bedeacylated on the aniline part to provided target compound 10.8.

The synthesis of compounds no 293 was carried out according to scheme 11

Boronic acid 12.1 is reacted with 12.2 using Suzuki coupling to afford12.3. This latter is reduced by hydrogenation in the presence of Pd/C tofurnish 12.4, which is further acylated to provide desired compound no293.

Example 1: Synthesis of Compound No 45

The general procedure used for the synthesis of triazolopiperazinecompounds of the invention is detailed below using the synthesis of

compound no 45:(R)-(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone

To a solution of intermediate 3a (80 mg, 0.27 mmol) in 7 mL of DCM therewas added Et₃N (68 mg, 0.67 mmol) and then a solution of 4-fluorobenzoylchloride 6.1 in DCM (43 mg, 0.27 mmol). The solution was left stirringat room temperature for 2 h. The reaction mixture was washed with water,brine, dried over sodium sulfate and approximately ¾ of the volatileswere evaporated. Diethyl ether was added and the precipitate wasfiltered and dried to yield the title compound. Yield: 68 mg, 60%. LCMS:P=100%, rt=1.96 mn, (M+H)⁺: 420.1; chiral: 7.22 mn, ee=91%. ¹HNMR(DMSO-d⁶): δ: 8.4 ppm (s, 1H), 8.05 ppm (m, 2H), 7.6 ppm (m, 2H), 7.5ppm (m, 3H), 7.35 ppm (t, 2H), 5.7 ppm (br m, 1H), 4.8 ppm (dd, 1H), 4.3ppm (m, 1H), 4.1 ppm (br m, 1H), 3.7 ppm (m, 1H), 1.6 ppm (d, 3H).

Examples 2 to 84

The general procedure detailed in example 1 was used for the preparationof compounds in examples 2 to 84 starting from the appropriateintermediates or commercially available reagents. Example no, compoundno, compound names, triazolopiperazine intermediates 3 and acyl chlorideintermediates 4 are listed in Table 2A below.

TABLE 2A Triazolopiperazine Example_n° Compound_n° intermediae 3 Acylchloride intermediate 4 2 1 3b 4-fluorobenzoyl chloride 3 2 3b4-chlorobenzoyl chloride 4 3 3b 4c 5 4 3b 4d 6 5 3b 3,4-dichlorobenzoylchloride 7 6 3b 4-phenylbenzoyl chloride 8 7 3h 4-fluorobenzoyl chloride9 8 3o 4-fluorobenzoyl chloride 10 9 3c 4-fluorobenzoyl chloride 11 103d 4-fluorobenzoyl chloride 12 11 3e 4-fluorobenzoyl chloride 13 12 3f4-fluorobenzoyl chloride 14 13 3b 4e 15 14 3b 4a 16 15 3g4-fluorobenzoic chloride 17 16 3b 4-(4-fluorophenyl)benzoyl chloride 1817 3b 4f 19 18 3b 4g 20 19 3h 4-phenylbenzoyl chloride 21 20 3c4-phenylbenzoyl chloride 22 21 3b 4-(thiophen-2-yl)benzoyl chloride 2322 3i 4-fluorobenzoyl chloride 24 23 3j 4-fluorobenzoyl chloride 25 243k 4-fluorobenzoyl chloride 26 25 3l 4-fluorobenzoyl chloride 27 26 3o4-phenylbenzoyl chloride 28 27 3m 4-fluorobenzoyl chloride 29 28 3p4-fluorobenzoyl chloride 30 29 3q 4-fluorobenzoyl chloride 31 30 3r4-fluorobenzoyl chloride 32 31 3s 4-fluorobenzoyl chloride 33 32 3t4-fluorobenzoyl chloride 34 33 3u 4-fluorobenzoyl chloride 35 34 3v4-fluorobenzoyl chloride 36 35 3w 4-fluorobenzoyl chloride 37 36 3x4-fluorobenzoyl chloride 38 37 3y 4-fluorobenzoyl chloride 39 38 3z4-fluorobenzoyl chloride 40 39 3a1 4-fluorobenzoyl chloride 41 40 3b14-fluorobenzoyl chloride 42 41 3c1 4-fluorobenzoyl chloride 43 42 3d14-fluorobenzoyl chloride 44 43 3e1 4-fluorobenzoyl chloride 45 44 3f14-fluorobenzoyl chloride 46 46 3g1 4-phenylbenzoyl chloride 47 47 3h14-phenylbenzoyl chloride 48 48 3i1 4-fluorobenzoyl chloride 49 49 3i14-fluorobenzoyl chloride 50 50 3h1 4-fluorobenzoyl chloride 51 51 3j14-fluorobenzoyl chloride 52 52 3g1 4-fluorobenzoyl chloride 53 53 3g14-(4-fluorophenyl)benzoyl chloride 54 54 3o 4-(thiophen-2-yl)benzoylchloride 55 55 3c 4-(thiophen-2-yl)benzoyl chloride 56 56 3g14-(thiophen-2-yl)benzoyl chloride 57 57 3k1 4-fluorobenzoyl chloride 5858 3l1 4-fluorobenzoyl chloride 59 59 3n 4-fluorobenzoyl chloride 60 603m1 4-fluorobenzoyl chloride 61 61 3n1 4-fluorobenzoyl chloride 62 623o1 4-(thiophen-2-yl)benzoyl chloride 63 63 3o 4-(thiophen-3-yl)benzoylchloride 64 64 3o1 4-(thiophen-3-yl)benzoyl chloride 65 65 3n14-(thiophen-2-yl)benzoyl chloride 66 66 3l1 4-(thiophen-2-yl)benzoylchloride 67 67 3l1 4-phenylbenzoyl chloride 68 68 3p1 4-fluorobenzoylchloride 69 69 3h 4-(thiophen-2-yl)benzoyl chloride 70 70 3q14-fluorobenzoyl chloride 71 71 3r1 4-fluorobenzoyl chloride 72 72 3s14-phenylbenzoyl chloride 73 73 3t 4-(thiophen-2-yl)benzoyl chloride 7474 3t1 4-fluorobenzoyl chloride 75 75 3s1 4-fluorobenzoyl chloride 76 763q1 4-phenylbenzoyl chloride 77 77 3u1 4-fluorobenzoyl chloride 78 783q1 4-(thiophen-2-yl)benzoyl chloride 79 79 3u1 4-phenylbenzoyl chloride80 80 3u1 4-(thiophen-2-yl)benzoyl chloride 81 81 3b 1-naphthoylchloride 82 82 3b 4h converted to acyl chloride 83 83 3b 4i converted toacyl chloride 84 85 3v1 4-(thiophen-2-yl)benzoyl chloride

Example 85: Compound No 87 was Synthesized by Reacting Intermediate 3 hand 4-Fluorophenylsulfonyl Chloride Using Well Known SulfonylationConditions Examples 87 to 111

The general procedure detailed in example 1 was used for the preparationof compounds in examples 87 to 111 starting from the appropriateintermediates or commercially available reagents. Example no, compoundno, compound names, triazolopiperazine intermediates 3 and carboxylicacidacyl chloride intermediates 4 are listed in table 2B hereunder.

TABLE 2B Triazolopiperazine Acyl chloride Example_n° Compound_n°intermediate 3 intermediate 4 87 89 3h 4-fluorophenylacetyl chloride 8890 3h 5-phenylpicolinyl chloride 89 91 3h 6-phenylnicotinyl chloride 9092 3h 2-phenylpyrimidine-5- carbonyl chloride 91 93 3h 4-phenylcyclohexanecarbonyl chloride 92 95 3h 3-methylbutanoyl chloride 9396 3h 2-phenylbenzoyl chloride 94 98 3h 4-(pyrimidin-5-yl)benzoylchloride 95 100 3h 4-(pyrimidin-2-yl)benzoyl chloride 96 101 3h4-(pyrazin-2-yl)benzoic chloride 97 102 3h 4-(pyridazin-3-yl)benzoylchloride 98 103 3h 4′-cyano-[1,1′-biphenyl]- 4-carbonyl chloride 99 1043h 4-(2-oxopiperidin-1-yl) benzoyl chloride 100 105 3h4-morpholinobenzoyl chloride 101 106 3h 4-(3,5-dimethyl-1H-pyrazol-1-yl)benzoyl chloride 102 107 3w1 4-(thiophen-2-yl)benzoyl chloride 103108 3x1 4-(thiophen-2-yl)benzoyl chloride 104 109 3q13,4-dichlorobenzoyl chloride 105 110 3q1 3,4-difluorobenzoyl chloride106 111 3q1 3-chloro-4-fluorobenzoyl chloride 107 112 3q13-fluoro-4-chlorobenzoyl chloride 108 113 3q1 3,4,5-trifluorobenzoylchloride 109 114 3i1 4-(thiophen-2-yl)benzoyl chloride 110 135 3a4-(thiophen-2-yl)benzoyl chloride 111 136 3g1 4-(thiophen-2-yl)benzoylchloride

It was noted that synthesis from chiral intermediate 3 could lead tocompounds with low enantiomeric excess. It could therefore beadvantageous to make the synthesis of compounds of invention fromracemic building block 3 and perform further purification by chiralpreparative HPLC.

Example 112: Synthesis of Compound No 166

A variant to the general procedure used for the synthesis oftriazolopiperazine compounds of the invention is detailed below usingthe synthesis of compound no 166:(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone:

To a solution of intermediate 3o1 (500 mg, 1.50 mmol) in 20 mL ofanhydrous DCM was added 4-fluorobenzoyl chloride 6.1 (261 mg, 1.65 mmol)and Et₃N (0.625 mL, 455 mg, 4.49 mmol). The reaction mixture was stirredfor 2 h. Thereupon the reaction mixture was washed with water, and theextracted organic layer further washed with brine, dried over sodiumsulfate. Thereafter the volatiles were concentrated and diethyl etherwas added to precipitate the product. The filtered precipitate was thendried in vacuo. Yield: 630 mg, 100%. LCMS: P=100%, rt=8.2 min, (M+H)⁺:420.1. ¹HNMR (CDCl₃): δ: 8.3 ppm (s, 1H), 8.0 ppm (m, 2H), 7.5 ppm (m,5H), 7.2 ppm (t, 2H), 5.7 ppm (br m, 1H), 5.0 ppm (dd, 1H), 4.4 ppm (m,1H), 3.5 ppm (m, 1H), 1.6 ppm (d, 3H).

The general procedure variant detailed in example 112 was used for thepreparation of compounds in examples 113 to 257 starting from theappropriate intermediates or commercially available reagents.

Example no, compound no, compound names, triazolopiperazineintermediates 3 and acyl chloride intermediates 4 are listed in table 2Chereunder.

TABLE 2C Example_n° Compound_n° Triazolopiperazine intermediate 3 Acylchloride intermediate 4 113 115 chiral preparative HPLC of compound n°61114 118 chiral preparative HPLC of compound n°46 115 131 chiralpreparative HPLC of compound n°49 116 134 chiral preparative HPLC ofcompound n°53 117 144 chiral preparative HPLC of compound n°65 118 156chiral preparative HPLC of compound n°80 119 159 3y1 4-fluorobenzoylchloride 120 160 3z1 4-fluorobenzoyl chloride 121 161 3a24′-fluoro-[1,1′-biphenyl]- 4-carbonyl chloride 122 162 chiralpreparative HPLC of compound n°61 123 163 chiral preparative HPLC ofcompound n°65 124 164 chiral preparative HPLC of compound n°70 125 165chiral preparative HPLC of compound n°80 126 167 chiral preparative HPLCof compound n°166 127 168 chiral preparative HPLC of compound n°209 128169 chiral preparative HPLC of compound n°209 129 170 3q4-(thiophen-2-yl)benzoyl chloride 130 171 3b2 4-(thiophen-2-yl)benzoylchloride 131 172 3c2 4-fluorobenzoyl chloride 132 173 3b24-fluorobenzoyl chloride 133 174 3c2 4-(thiophen-2-yl)benzoyl chloride134 175 3d2 4-fluorobenzoyl chloride 135 176 3d24-(thiophen-2-yl)benzoyl chloride 136 177 3e2 4-(thiophen-2-yl)benzoylchloride 137 178 3f2 4-fluorobenzoyl chloride 138 179 3f24-(thiophen-2-yl)benzoyl chloride 139 180 3g2 4-fluorobenzoyl chloride140 181 3g2 4-(thiophen-2-yl)benzoyl chloride 141 182 3g24-phenylbenzoyl chloride 142 183 3g2 4′-fluoro-[1,1′-biphenyl]-4-carbonyl chloride 143 185 3h2 4-(thiophen-2-yl)benzoyl chloride 144186 3h2 4-phenylbenzoyl chloride 145 187 3h2 4′-fluoro-[1,1′-biphenyl]-4-carbonyl chloride 146 188 3i2 4-fluorobenzoyl chloride 147 189 3i24-(thiophen-2-yl)benzoyl chloride 148 190 3j2 4-fluorobenzoyl chloride149 191 3j2 4-(thiophen-2-yl)benzoyl chloride 150 192 3j24-phenylbenzoyl chloride 151 193 3k2 4-fluorobenzoyl chloride 152 1943k2 4-(thiophen-2-yl)benzoyl chloride 153 195 3k2 4-phenylbenzoylchloride 154 196 3k2 4′-fluoro-[1,1′-biphenyl]- 4-carbonyl chloride 155198 3l2 4-(thiophen-2-yl)benzoyl chloride 156 199 3l2 4-phenylbenzoylchloride 157 200 3l2 4′-fluoro-[1,1′-biphenyl]- 4-carbonyl chloride 158201 3m2 4-fluorobenzoyl chloride 159 202 3m2 4-(thiophen-2-yl)benzoylchloride 160 203 3m2 4-phenylbenzoyl chloride 161 204 3d24-phenylbenzoyl chloride 162 205 3d2 4′-fluoro-[1,1′-biphenyl]-4-carbonyl chloride 163 206 3n2 4-fluorobenzoyl chloride 164 207 3n24-(thiophen-2-yl)benzoyl chloride 165 208 3o2 4-fluorobenzoyl chloride166 209 3p2 4-(thiophen-2-yl)benzoyl chloride 167 211 3q24-(thiophen-2-yl)benzoyl chloride 168 212 3q2 4-fluorobenzoyl chloride169 213 3r2 4-(thiophen-2-yl)benzoyl chloride 170 214 3r24-fluorobenzoyl chloride 171 215 3q1 4-(5-methylthiophen-2-yl) benzoylchloride 4-(5-methylthiophen-2-yl)benzoyl chloride was prepared from aclassical Suzuki coupling between 2-bromo-5-methylthiophene and4-methoxycarbonylphenylboronic acid followed by a saponification andacyl chloride formation 172 216 3q1 4-c yanobenzoyl chloride 173 217 3c24-phenylbenzoyl chloride 174 218 3s2 4-fluorobenzoyl chloride 175 2193t2 4-(thiophen-2-yl)benzoyl chloride 176 220 3u24-(thiophen-2-yl)benzoyl chloride 177 221 3v2 4-fluorobenzoyl chloride178 222 3w2 4-(thiophen-2-yl)benzoyl chloride 179 223 3x24′-fluoro-[1,1′-biphenyl]- 4-carbonyl chloride 180 224 3y24-(thiophen-2-yl)benzoyl chloride 181 225 3u2 4-fluorobenzoyl chloride182 226 3z2 4-(thiophen-2-yl)benzoyl chloride 183 227 chiral preparativeHPLC of compound n°56 184 228 3s2 4-(thiophen-2-yl)benzoyl chloride 185229 3v2 4-(thiophen-2-yl)benzoyl chloride 186 230 3y2 4-fluorobenzoylchloride 187 231 3b benzoyl chloride 188 232 3b 4-methylbenzoyl chloride189 304 3q1 4-(2-methylthiophen-3-yl) benzoyl chloride4-(2-methylthiophen-3-yl)benzoyl chloride was prepared from a classicalSuzuki coupling between methyl 4-iodobenzoate &4,4,5,5-tetramethyl-2-(2-methylthiophen-3-yl)- 1,3,2-dioxaborolanefollowed by a saponification and acyl chloride formation 190 233 chiralpreparative HPLC of compound n°4 191 234 chiral preparative HPLC ofcompound n°4 192 235 3a3 4-(thiophen-2-yl)benzoyl chloride 193 236Cyanation of compound n°213 using the procedure described inWO2008/103500 A1 194 237 3a3 4-fluorobenzoyl chloride 195 238 3w24-fluorobenzoyl chloride 196 239 3b3 4-(thiophen-2-yl)benzoyl chloride197 240 3b3 4-fluorobenzoyl chloride 198 241 3c34-(thiophen-2-yl)benzoyl chloride 199 242 3c3 4-fluorobenzoyl chloride200 244 3d3 4-fluorobenzoyl chloride 201 245 3e34-(thiophen-2-yl)benzoyl chloride 202 246 3e3 4-fluorobenzoyl chloride203 247 3f3 4-(thiophen-2-yl)benzoyl chloride 204 248 3g34-(thiophen-2-yl)benzoyl chloride 205 249 3g3 4-fluorobenzoyl chloride206 250 3h3 4-(thiophen-2-yl)benzoyl chloride 207 251 3h34-fluorobenzoyl chloride 208 252 3i3 4-(thiophen-2-yl)benzoyl chloride209 253 3t 4-(dimethylamino)benzoyl chloride 210 254 3j34-(thiophen-2-yl)benzoyl chloride 211 255 3j3 4-fluorobenzoyl chloride212 256 3k3 4-(thiophen-2-yl)benzoyl chloride 213 257 3134-(thiophen-2-yl)benzoyl chloride 214 258 3m3 4-fluorobenzoyl chloride215 259 3k3 4-fluorobenzoyl chloride 216 260 2-(4-fluorophenyl)-4-4-fluorobenzoyl chloride (5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazole2-(4-fluorophenyl)-4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)thiazolewas synthesized using the procedure described by T.G. Murali Dhar etal.in Bioorg. Med. Chem. Lett. 17(2007) 5019-24 217 261 3n34-(thiophen-2-yl)benzoyl chloride 218 262 2o3 4-(thiophen-2-yl)benzoylchloride 219 263 3l3 4-(thiophen-2-yl)benzoyl chloride 220 265 3p34-(thiophen-2-yl)benzoyl chloride 221 266 3q3 4-(thiophen-2-yl)benzoylchloride 222 267 3r3 4-(thiophen-2-yl)benzoyl chloride 223 268 3q14-(3-methylthiophen-2-yl) benzoyl chloride4-(3-methylthiophen-2-yl)benzoyl chloride was prepared from a classicalSuzuki coupling between methyl 4-iodobenzoate &4,4,5,5-tetramethyl-2-(3-methylthiophen-2-yl)- 1,3,2-dioxaborolanefollowed by a saponification and acyl chloride formation 224 269 3r34-fluorobenzoyl chloride 225 270 chiral preparative HPLC of compoundn°268 226 271 3o3 4-fluorobenzoyl chloride 227 272 chiral preparativeHPLC of compound n°268 228 273 3s3 4-(thiophen-2-yl)benzoyl chloride 229274 3t3 4-(thiophen-2-yl)benzoyl chloride 230 275 3u34-(thiophen-2-yl)benzoyl chloride 231 276 3t3 4-fluorobenzoyl chloride232 277 3v3 4-fluorobenzoyl chloride 233 278 3w3 4-fluorobenzoylchloride 234 279 3v3 4-(thiophen-2-yl)benzoyl chloride 235 280 Compoundn°262 was alkylated with tert-butyl (2-bromoethyl) carbamate using thesame alkylation procedure that is described in General Method H 236 281Compound n°262 was alkylated with 2-(2-bromoethoxy) tetrahydro-2H-pyranusing the same alkylation procedure that is described in General MethodH, then the THP group was removed with HCl in dioxane 237 282 Compoundn°280 was treated with TFA in DCM (Boc deprotection) 238 283 Accordingto scheme 10 239 284 Compound n°267 was alkylated with2-(2-bromoethoxy)tetrahydro-2H-pyran 285 using the same alkylationprocedure that is described in General Method H, then the THP group wasremoved with HCl in dioxane. Chiral preparative HPLC yielded compoundsn° 284 and 285 240 286 3w3 4-phenylbenzoyl chloride 241 287 3w34-(thiophen-2-yl)benzoyl chloride 242 288 Compound n°275 was reactedwith 2,4-difluoro-iodobenzene according to General Method F(C2-arylation described in Org. Lett. 2008, 10 (13), 2909) 243 289According to scheme 10 244 290 According to scheme 10 245 291 Accordingto scheme 10 246 292 According to scheme 10 247 293 According to scheme11 248 294 3t 4c 249 295 3t 4h 250 296 3t 4a 251 297 3t 4i 252 298Compound n°267 was alkylated with tert-butyl (2-bromoethyl) carbamateusing the same alkylation procedure that is 299 described in GeneralMethod H, Chiral preparative HPLC yielded compounds n°284 and 285 253300 3x3 4-(thiophen-2-yl)benzoyl chloride 254 301 2y34-(thiophen-2-yl)benzoyl chloride 255 302 Compound n° 300 was convertedto compound n° 302 using the cyanation procedure described inWO2008/103500 A1 256 303 Compound n° 301 was converted to compound n°303 using the cyanation procedure described in WO2008/103500 A1 257 2433d3 4-(thiophen-2-yl)benzoyl chloride

BIOLOGY EXAMPLES Brief Description of the Drawings

FIG. 1 shows the effects of a single intravenous 10 mg/kg dose ofcompound no 156 on LH serum levels in castrated male rats, measured 60min and 120 min following dosing. LH hormone levels are expressed asmeans±S.E.M. (**p<0.001 vs. baseline, determined by one-Way ANOVA andDunnett's post hoc).

FIG. 2 shows the effects of a single intravenous dose of compound no 144(10 mg/kg), compound 71 (15 mg/kg) and compound 114 (20 mg/kg) on LHserum levels in castrated male rats, measured 60 min following dosing.LH hormone levels are expressed as means±S.E.M. (**p<0.001 vs. baseline,determined by one-Way ANOVA and Dunnett's post hoc).

FIG. 3 shows the effect of a single intravenous 20 mg/kg dose ofcompound no 156 on testosterone plasma levels in gonad-intact male rats(N=5 rats/group). Plasma testosterone levels are represented as anintegrated testosterone response (AUC) over a 420 min period followingdosing.

COMPETITIVE BINDING ASSAYS

The affinity of compounds of the invention for the tachykinin receptorswas determined by measuring the ability of the compounds of theinvention to displace a radiolabeled ligand from its specifics bindingsite.

³H-SB222200 Binding Competition Assay with Human NK-3 Receptor

The ability of the compounds of the invention to inhibit the binding ofthe NK-3 receptor selective antagonist SB222200 was assessed by an invitro radioligand binding assay. Membranes were prepared from Chinesehamster ovary recombinant cells which express the human NK3 receptor.The membranes were incubated with 5 nM ³H-SB222200_(ARC) in a HEPES 25mM/NaCl 0.1M/CaCl₂ 1 mM/MgCl₂ 5 Mm/BSA 0.5%/Saponin 10 μg/ml buffer atpH 7.4 and various concentrations of the compounds of the invention. Theamount of tritiated SB222200 bound to the receptor was determined afterfiltration by the quantification of membrane associated radioactivityusing the TopCount-NXT reader (Packard). Competition curves wereobtained for compounds of the invention and the concentrations ofcompounds which displaced 50% of bound radioligand (IC₅₀) weredetermined and then apparent inihibition constant Ki values werecalculated by the following equation: Ki=IC₅₀/(1+[L]/K_(D)) where [L] isthe concentration of free radioligand and K_(D) is its dissociationconstant at the receptor, derived from saturation binding experiments(Cheng and Prusoff, 1973) (see results in table 3 below).

In Table 3 biological results obtained using the ³H-SB222200 bindingcompetition assay with compounds of the invention are set out intabulated form. In this table the calculated Ki is given. The Ki valueobtained (in accordance with the protocol set forth above) isrepresented as follows: “+++” means Ki<500 nM; “++” means 500 nM≤Ki≤1μM; “+” means 1 μM<Ki≤5 μM; “#” means Ki>5 μM.

TABLE 3 Compound Ki n° range 1 + 2 + 3 + 4 + 5 + 6 + 7 +++ 8 +++ 9 +++10 +++ 11 +++ 13 + 14 + 15 + 16 + 17 + 18 + 19 +++ 20 +++ 21 +++ 22 ++23 ++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33+++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 ++ 40 +++ 41 +++ 42 +++ 43 +44 + 45 +++ 46 +++ 47 +++ 48 +++ 49 +++ 50 +++ 51 +++ 52 +++ 53 +++ 54+++ 55 +++ 56 +++ 57 +++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64+++ 65 +++ 66 +++ 67 +++ 68 +++ 69 +++ 70 +++ 71 +++ 72 +++ 73 +++ 74+++ 75 ++ 76 +++ 77 +++ 78 +++ 79 +++ 80 +++ 83 # 85 +++ 90 +++ 91 +++92 + 93 + 95 + 96 # 103 + 107 ++ 108 ++ 109 +++ 110 +++ 111 +++ 112 +++113 +++ 114 +++ 115 +++ 118 +++ 131 +++ 134 +++ 135 +++ 136 +++ 144 +++156 +++ 159 # 160 + 161 + 162 +++ 163 ++ 164 +++ 165 +++ 166 +++ 167 ++168 +++ 169 +++ 170 +++ 171 +++ 172 +++ 173 +++ 174 +++ 175 +++ 176 +++177 +++ 178 + 179 +++ 180 +++ 181 +++ 182 +++ 183 +++ 185 # 186 + 187 +188 ++ 189 +++ 190 +++ 191 # 193 +++ 194 +++ 195 +++ 196 +++ 198 + 199 +200 ++ 201 + 202 +++ 203 ++ 204 +++ 205 ++ 206 + 207 +++ 208 + 209 +++211 +++ 212 +++ 213 +++ 214 +++ 215 +++ 216 +++ 217 +++ 218 + 219 +++220 +++ 221 ++ 222 +++ 223 +++ 224 +++ 225 + 226 # 227 ++ 228 +++ 229+++ 230 + 231 + 232 + 233 +++ 234 +++ 235 +++ 236 +++ 238 +++ 239 + 240++ 241 +++ 242 ++ 244 ++ 245 +++ 246 +++ 247 +++ 248 +++ 249 +++ 250 ++252 ++ 253 ++ 254 +++ 255 ++ 256 +++ 257 +++ 258 +++ 259 + 260 +++ 261+++ 262 +++ 263 +++ 265 +++ 266 +++ 267 +++ 268 +++ 269 ++ 271 +++ 273+++ 274 ++ 275 # 276 # 277 # 278 +++ 279 +++ 280 +++ 281 +++ 282 ++ 283++ 284 +++ 285 +++ 286 +++ 287 +++[¹²⁵]-his-MePhe7-Neurokinin B Binding Competition Assay with Rat NK-3Receptor

The affinity of compounds of the invention for the rat NK3 receptor wasevaluated in CHO recombinant cells which express the rat NK3 receptor.Membrane suspensions were prepared from these cells. The followingradioligand: [¹²⁵I]-His-MePhe7-Neurokinin B (PerkinElmer Cat # NEX285)was used in this assay. Binding assays were performed in a 25 nM HEPES/1mM CaCl₂/5 mM MgCl₂/0.5% BSA/10 μg/ml Saponin, at pH 7.4. Binding assaysconsisted of 25 l of membrane suspension (approximately 5 μgprotein/well in a 96 well plate), 50 μl of compound or reference ligand(MePhe7-Neurokinin B) at increasing concentrations (diluted in assaybuffer) and 0.09 nM [¹²⁵I]-His-MePhe7-Neurokinin B. The plate wasincubated 60 min at 25° C. in a water bath and then filtered over GF/Cfilters (Perkin Elmer, 6005174, presoaked in assay buffer withoutsaponine for 2 h at room temperature) with a Filtration unit (PerkinElmer). The radioactivity retained on the filters was measured by usingthe TopCount-NXT reader (Packard). Competition curves were obtained forcompounds of the invention and the concentrations of compounds whichdisplaced 50% of bound radioligand (IC₅₀) were determined and thenapparent inhibition constant Ki values were calculated by the followingequation: Ki=IC₅₀/(1+[L]/K_(D)) where [L] is the concentration of freeradioligand and K_(D) is its dissociation constant at the receptor,derived from saturation binding experiments (Cheng and Prusoff, 1973).

When tested in above described assay, preferred compounds of theinvention showed an inhibition constant (Ki) for rat NK-3 receptor <50nM.

Selectivity Assay

Selectivity of the compounds of the invention was determined over theother human NK receptors, namely NK-1 and NK2 receptors.

Human NK1

The affinity of compounds of the invention for the NK1 receptor wasevaluated in CHO recombinant cells which express the human NK1 receptor.Membrane suspensions were prepared from these cells. The followingradioligand: [³H] substance P (PerkinElmer Cat # NET111520) was used inthis assay. Binding assays were performed in a 50 mM Tris/5 mM MnCl2/150mM NaCl/0.1% BSA at pH 7.4. Binding assays consisted of 25 μl ofmembrane suspension (approximately 5 μg of protein/well in a 96 wellplate), 50 μl of compound or reference ligand (Substance P) atincreasing concentrations (diluted in assay buffer) and 2 nM [³H]substance P. The plate was incubated 60 min at 25° C. in a water bathand then filtered over GF/C filters (Perkin Elmer, 6005174, presoaked in0.5% PEI for 2 h at room temperature) with a Filtration unit (PerkinElmer). The radioactivity retained on the filters was measured by usingthe TopCount-NXT reader (Packard). Competition curves were obtained forcompounds of the invention and the concentrations of compounds whichdisplaced 50% of bound radioligand (IC₅₀) were determined and thenapparent inhibition constant Ki values were calculated by the followingequation: Ki=IC₅₀/(1+[L]/K_(D)) where [L] is the concentration of freeradioligand and K_(D) is its dissociation constant at the receptor,derived from saturation binding experiments (Cheng and Prusoff, 1973).

Human NK2

The affinity of compounds of the invention for the NK2 receptor wasevaluated in CHO recombinant cells which express the human NK2 receptor.Membrane suspensions were prepared from these cells. The followingradioligand [¹²⁵I]-Neurokinin A (PerkinElmer Cat # NEX252) was used inthis assay. Binding assays were performed in a 25 mM HEPES/1 mM CaCl2/5mM MgCl2/0.5% BSA/10 μg/ml saponin, at pH 7.4. Binding assays consistedof μl of membrane suspension (approximately 3.75 μg of protein/well in a96 well plate), 50 μl of compound or reference ligand (Neurokinin A) atincreasing concentrations (diluted in assay buffer) and 0.1 nM[¹²⁵I]-Neurokinin A. The plate was incubated 60 min at 25° C. in a waterbath and then filtered over GF/C filters (Perkin Elmer, 6005174,presoaked in assay buffer without saponine for 2 h at room temperature)with a Filtration unit (Perkin Elmer). The radioactivity retained on thefilters was measured by using the TopCount-NXT reader (Packard).Competition curves were obtained for compounds of the invention and theconcentrations of compounds which displaced 50% of bound radioligand(IC₅₀) were determined and then apparent inhibition constant Ki valueswere calculated by the following equation: Ki=IC₅₀/(1+[L]/K_(D)) where[L] is the concentration of free radioligand and K_(D) is itsdissociation constant at the receptor, derived from saturation bindingexperiments (Cheng and Prusoff, 1973).

The compounds of the invention, which were tested in the above NK-1 andNK-2 described assays, demonstrated a low affinity at the human NK-1 andhuman NK-2 receptors: 100-200 fold shift of the Ki compared to the humanNK-3 receptor. Thus, compounds according to the invention have beenshown to be selective over NK1 and NK2 receptors.

In Vivo Assay to Assess Compound Activity in Rat

The inhibitory effect of the compounds of the invention in luteinizinghormone (LH) secretion and on circulating steroid levels are determinedby the following biological studies.

Castrated Male Rat Model to Assess the Effect of Compound of Inventionon Circulating Levels of Luteinizing Hormone (LH).

In humans and rodents, castration is well-precedented to permitheightened, persistent GnRH signaling and consequently elevation ofcirculating LH. Thus, in this animal model, LH is measured in castratedrats as a marker of test compound inhibition of the GnRH signalingpathway.

Castrated adult male Sprague-Dawley (SD) rats (150-175 g,) werepurchased from Janvier (St Berthevin, France). All animals were housed 3per cage in a temperature-controlled room (22±2° C.) and 50±5% relativehumidity with a 12 hour light/12 hour dark photoperiod (lights off at 6h00 pm). The animals were allowed 2 weeks of postoperative recoveryprior to study. Animals were handled on a daily basis. Standard diet andtap water were provided ad libitum. Animal cage litters were changedonce a week. On the study day, animals were acclimated to the procedureroom for a period of one hour prior to the initiation of the experiment.

Compounds of the invention were formulated as 10% DMSO, 10% CremophoreEL, and 80% saline solutions.

After basal sampling (TO) a single dose of compounds of the invention orvehicule was administrated intravenously to rats. Blood was thencollected at 60 min and 120 min post dosing. Blood samples were obtainedvia tail vein bleed, drawn into EDTA-containing tubes and centrifugedimmediately. Plasma samples were collected and stored in a −80° C.freezer until assayed. Serum LH levels were determined usingradioimmunoassay kit from IDS (Libge, Belgium). Baseline was defined asthe initial basal blood sample.

When tested in the castrated male rat model described above, thecompounds no 144, 71, 156 and 114 significantly suppressed GnRH-mediatedelevation of LH (FIGS. 1 and 2).

This result also shows that the compounds according to the inventionpass through the blood-brain barrier and that they are capable ofblocking the action of the NK-3 receptors in the CNS. The brain toplasma ratio values (B/P) obtained with the compounds according to theinvention were generally greater than 0.1 indicating a significant brainpenetration.

Gonad-Intact Adult Male to Assess the Effect of Compounds of theInvention on Circulating Levels of Testosterone.

Gonad-intact adult male Sprague-Dawley (SD) rats (300-385 g N=5/groupwere single housed in a temperature-controlled room (22±2° C.) and 50±5%relative humidity with a 12 hour light/12 hour dark photoperiod (lightsoff at 6 h00 μm). Purina rat chow (Ralston Purina Co., St. Louis, Mo.)and tap water were made available to rats, ad libitum. Chronicintracardiac venous cannulae were implanted under sodium pentobarbitalanaesthesia (50 mg/kg, i.p.). After surgery, rats were placed directlyinto isolation test chambers and provided with food and water ad libitumuntil body weight returned to preoperative levels (a period of at leastfive days). On the test day, food was removed 1.5 h before the start ofsampling and was returned at the end of the experiment. After basalblood sampling, free-moving rats were intravenously injected at time=0min with either a single dose (20 mg/kg) of compound no 156 or vehicle.Blood was then collected through a heparinized line at regular intervalsup to 420 min and centrifuged immediately. Plasma samples were collectedand stored in a −80° C. freezer until assayed. Plasma testosteronelevels were determined using a radioimmunoassay kit (Immunotech).

Compound no 156 was formulated as 40% DMA, 50% PEG400, and 10% sterilewater solution.

When tested in gonad-intact male rats, compound no 156 significantlysuppressed plasma testosterone levels over the 420 minute test period(FIG. 3).

1-16. (canceled)
 17. A medicament comprising a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein Ar¹ is a 5- to 6-membered aryl or heteroaryl group, 3-to 6-membered cycloalkyl group, a 3- to 6-membered heterocyclyl group ora C3-C6 alkyl group, each of the aryl, heteroaryl, cycloalkyl orheterocyclyl groups being optionally substituted by one or more group(s)selected from halo, cyano, alkyl, haloalkyl, cycloalkyl, heteroalkyl,heterocyclyl, aryl, aralkyl, heteroaryl, hydroxyl, alkoxy, haloalkoxy,alkoxyalkoxy, alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl,carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino,or two substituents form an alkylenedioxy group or a haloalkylenedioxygroup, or two substituents form a cycloalkyl or heterocycloalkyl moietytogether with the cycloalkyl or heterocycloalkyl group they are attachedto, or fused to the aryl, heteroaryl, cycloalkyl or heterocycloalkylgroup may be one or more aryl moiety, each of said substituents beingoptionally substituted by one or more further substituent(s) selectedfrom halo, cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy,heterocyclyl, aryl, heteroaryl, aryloxy heteroaryloxy; L¹ is C₁-C₂alkylene optionally being substituted by one or more group(s) selectedfrom halo, methyl or ethyl under the condition that R^(2′) together withR² form an oxo substituent, or L¹ is carbonyl or sulfonyl, or L¹ is—(C═O)—CH₂— where the C═O is linked to the piperazine nitrogen and theCH₂ to Ar¹; R¹ is H, a C₁-C₄ alkyl, aryl or aralkyl group, each of saidalkyl, aryl or aralkyl groups being optionally substituted by one ormore group(s) selected from halo or hydroxyl; R^(1′) is H or a C₁-C₄alkyl group; R² is H or a C₁-C₄ alkyl group; R^(2′) is H or a C₁-C₄alkyl group, or, when L¹ is C₁-C₂ alkylene optionally being substitutedby one or more group(s) selected from halo, methyl or ethyl, R^(2′)together with R² form an oxo substituent; R³ is H or a C₁-C₄ alkyl groupoptionally substituted by one hydroxy; R^(3′) is H or a C₁-C₄ alkylgroup; X¹ and X² are independently N; L² is a single bond or carbonyl,Ar² is a 5- to 6-membered aryl or heteroaryl group, each of the aryl, orheteroaryl groups being optionally substituted by one or more group(s)selected from halo, cyano, alkyl, hydroxyalkyl, haloalkyl, cycloalkyl,heteroalkyl, heterocyclyl, aryl, heteroaryl, aralkyl, heteroarylalkyl,hydroxyl, alkoxy, haloalkoxy, alkylamino, carboxy, alkoxycarbonyl,alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, acylamino,carbamoyl, alkylcarbamoyl, carbamoylalkyl, carbamoylamino,alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,arylsulfonylalkyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,haloalkylsulfonylamino, or two substituents form an alkylenedioxy groupor a haloalkylenedioxy group, or fused to the aryl or heteroaryl groupmay be one or more cycloalkyl, aryl, heterocyclyl or heteroaryl moiety,each of said substituents being optionally substituted by one or morefurther substituent(s) selected from halo, cyano, alkyl, haloalkyl,alkoxy, haloalkoxy, cycloalkyl, heterocyclyl optionally substituted byalkyl, aryl, heteroaryl, hydroxyl, alkoxyalkyl, hydroxyalkoxy,alkylamino, alkylsulfonylamino, alkoxycarbonylamino, aminoalkoxy, oralkoxycarbonylaminoalkoxy; and wherein, when: R¹, R^(1′), R², R^(2′),R³, R^(3′) are H, and L¹ is carbonyl, and L² is single bond, and Ar¹ isa 6-membered aryl optionally substituted by one or more group(s)selected from halo, cyano, C1-C3 alkyl, C1 haloalkyl, and Ar² is a 5- to6-membered aryl or heteroaryl group optionally substituted by one ormore group(s) selected from halo, C1-C3 alkyl, hydroxyl, methoxy, orfused to an aryl or heteroaryl group optionally substituted by one ormore further halo, C1-C3 alkyl, hydroxyl, methoxy, then, Ar¹ is phenyl,3-halophenyl, 4-halophenyl, 2,3-dichlorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl, 2,5-dihalophenyl, 2,6-difluorophenyl,2,6-dichlorophenyl, 3,4-dihalophenyl, 3,5-dihalophenyl,3,4,5-trihalophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl,2,3-dicyanophenyl, 2,4-dicyanophenyl, 3,5-dicyanophenyl,3-cyano-4-halophenyl, 4-(C1-C3 alkyl)phenyl, 3,4-di(C1-C3 alkyl)phenyl,3,5-di(C1-C3 alkyl)phenyl, 4-(C1 haloalkyl)phenyl, and Ar² is,quinolin-2-yl, isoquinolin-3-yl, 8-haloquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl; with the following provisos:Ar¹ is neither a substituted or unsubstituted pyrazolo[1,5-a]pyridin-2ylnor a substituted or unsubstituted pyrazolo[1,5-a]pyrimidin-2yl moiety.18. The medicament according to claim 17 comprising a compound offormula Ib

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein Ar¹, Ar², R¹, R^(1′) R², R^(2′), R³, R^(3′) X¹, X²,are as defined in claim
 17. 19. The medicament according to claim 18comprising a compound of formula Ic

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein a depicts the bond linking R¹ to the piperazinemoiety, and Ar¹, Ar², R¹, R^(1′), X¹, and X² are as defined in claim 18.20. The medicament according to claim 19 comprising a compound selectedfrom formulae Id-1, Id-2, Id-3 and Id-4

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein a depicts the bond linking R¹ to the piperazinemoiety; and Ar², R¹, X¹ and X² are as defined in claim 18; and R⁴,R^(4′), R⁵, R^(5′) and R⁶ are independently selected from H, halo,cyano, alkyl, haloalkyl, C3-C6 cycloalkyl, heteroalkyl, heterocyclyl,aryl, heteroaryl, hydroxyl, alkoxy, haloalkoxy, alkoxyalkoxy,alkylamino, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl,carbamoylamino, alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl,sulfamoyl, alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino,or R⁵ together with R⁴ or R⁶, or R^(5′) together with R^(4′) or R⁶ formsan alkylenedioxy group or a haloalkylenedioxy group, or R⁵ together withR⁴ or R⁶, or R^(5′) together with R^(4′) or R⁶ forms an aryl moietyfused to the phenyl group to which they are attached, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl;and R⁷ is H or methyl; and R^(7′) is H or methyl; and Ar⁴ is acycloalkyl or an aryl group, each of said cycloalkyl or aryl groupsbeing optionally substituted by one or more group(s) selected from halo,alkyl, haloalkyl, cyclopropyl, haloalkoxy, aryloxy; and M¹ is N orC—R^(4″) wherein R^(4″) is selected from H, halo, cyano, alkyl,haloalkyl, C3-C6 cycloalkyl, heteroalkyl, heterocyclyl, aryl,heteroaryl, hydroxyl, alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino,carboxy, alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,haloalkylcarbonylamino, carbamoyl, alkylcarbamoyl, carbamoylamino,alkylcarbamoylamino, alkylsulfonyl, haloalkylsulfonyl, sulfamoyl,alkylsulfamoyl, alkylsulfonylamino, haloalkylsulfonylamino, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl;and M² is N or M² is C—R^(5″) under the condition that M¹ is N, whereinR^(5″) is selected from H, halo, cyano, alkyl, haloalkyl, C3-C6cycloalkyl, heteroalkyl, heterocyclyl, aryl, heteroaryl, hydroxyl,alkoxy, haloalkoxy, alkoxyalkoxy, alkylamino, carboxy, alkoxycarbonyl,alkylcarbonyloxy, alkylcarbonylamino, haloalkylcarbonylamino, carbamoyl,alkylcarbamoyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,haloalkylsulfonylamino, or R^(5″) together with R⁶ forms analkylenedioxy group or a haloalkylenedioxy group, or an aryl moietyfused to the pyridinyl group to which they are attached, each of saidsubstituents being optionally substituted by one or more furthersubstituent(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl;and wherein, in formula Id-1 when: R¹ is H, and R⁴, R^(4′), R⁵, R^(5′)and R⁶ are independently selected from H, halo, cyano, C1-C3 alkyl, C1haloalkyl, and Ar² is a 5- to 6-membered aryl or heteroaryl groupoptionally substituted by one or more group(s) selected from halo, C1-C3alkyl, hydroxyl, alkoxy, or fused to an aryl group optionallysubstituted by one or more further halo, C1-C3 alkyl, hydroxyl, methoxythen, R⁴, R^(4′), R⁵, R^(5′) and R⁶ are H, or R⁴, R^(4′), R^(5′), R⁶ areH and R⁵ is halo, or R⁴, R^(4′), R⁵, R^(5′) are H and R⁶ is halo, cyano,C1-C3 alkyl, C1 haloalkyl, or R^(4′), R^(5′), R⁶ are H and R⁴, R⁵ arehalo, or R⁴, R^(4′), R^(5′) are H and R⁵, R⁶ are independently halo, orR⁴, R^(4′) are H and R⁵, R^(5′), R⁶ are halo, and Ar² is, quinolin-2-yl,isoquinolin-3-yl, 8-haloquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl.
 21. The medicament accordingto claim 20 comprising a compound selected from formulae Ie-1, Ie-2 andIe-3

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein a depicts the bond linking R¹ to the piperazinemoiety; and Ar², R¹, X¹ and X² are as defined in claim 18; and R⁵ and R⁶are independently selected from H, halo, cyano, alkyl, cyclopropyl,aryl, heteroaryl, each of said aryl and heteroaryl groups beingoptionally substituted by one or more group(s) selected from halo,alkyl, cyclopropyl, or R⁵ and R⁶ together form a phenyl moiety fused tothe phenyl ring they are attached to; and R⁸, R^(8′), R⁹, R^(9′) and R¹⁰are independently selected from H, halo, haloalkyl, cyclopropyl orhaloalkoxy, or R⁸, R^(8′), R⁹, R^(9′) are H and R¹⁰ is phenoxy; M¹ andM² are as defined in claim 20; and wherein, in formula Ie-1 when: R¹ isH, and R⁵ and R⁶ are independently selected from H, halo, cyano, C1-C3alkyl, and Ar² is a 5- to 6-membered aryl or heteroaryl group optionallysubstituted by one or more group(s) selected from halo, C1-C3alkyl,hydroxyl, alkoxy, or fused to an aryl group optionally substituted byone or more further halo, C1-C3 alkyl, hydroxyl, methoxy then, R⁶ is Hand R⁵ is H, halo, or R⁵ is H and R⁶ is halo, cyano, C1-C3 alkyl, C1haloalkyl, or R⁵ and R⁶ are independently halo, and Ar² is,quinolin-2-yl, isoquinolin-3-yl, 8-haloquinolin-2-yl, benzothiazol-2-yl,4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl.
 22. The medicament accordingto claim 19 comprising a compound selected from formulae If-1, If-2,If-3, If-4, If-5, If-6, If-7 and If-8

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein a designates the bond linking R¹ to the piperazinemoiety; and Ar¹, R¹, X¹ and X² are as defined in claim 18; and R¹¹, R¹²,R^(12′) and R¹³ are independently selected from H, halo, cyano, alkyl,hydroxyalkyl, haloalkyl, C3-C6 cycloalkyl, heteroalkyl, heterocyclyl,aryl, heteroaryl, -hydroxyl, alkoxy, haloalkoxy, alkylamino, carboxy,alkoxycarbonyl, alkylcarbonyloxy, alkylcarbonylamino,haloalkylcarbonylamino, acylamino, carbamoyl, alkylcarbamoyl,carbamoylalkyl, carbamoylamino, alkylcarbamoylamino, alkylsulfonyl,haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl, alkylsulfonylamino,haloalkylsulfonylamino, or R¹² together with R¹¹ or R¹³, or R¹³ togetherwith R^(12′) forms an alkylenedioxy group or a haloalkylenedioxy group,or R¹² together with R¹¹ or R¹³ forms a cycloalkyl, aryl, heterocyclylor heteroaryl moiety fused to the pyridyl group to which they areattached, each of said groups being optionally substituted by one ormore group(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,alkoxy, haloalkoxy or hydroxyl; and Ar⁵ is a heterocyclyl, aryl,heteroaryl, aralkyl, heteroarylalkyl, or arylsulfonylalkyl group, eachof which being optionally substituted by one or more group(s) selectedfrom halo, cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy,heterocyclyl optionally substituted by alkyl, aryl, hydroxyl, alkoxy,alkoxyalkyl, hydroxyalkoxy, alkylamino, alkylsulfonylamino, aminoalkoxy,or alkoxycarbonylaminoalkoxy; and X³ is O or S; and R¹⁴ is H or methyl;and Ar⁶ is a heterocyclyl, aryl or heteroaryl group, each of which beingoptionally substituted by one or more group(s) selected from halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy, aryl orhydroxyl; and R¹⁵ is H or methyl; and R¹⁶ is a heterocyclyl, aryl orheteroaryl group, each of said groups being optionally substituted byone or more group(s) selected from halo, cyano, alkyl, haloalkyl,cyclopropyl, alkoxy, haloalkoxy or hydroxyl; R¹⁷ is H, methyl or R¹⁷together with R¹⁶ forms a cycloalkyl or aryl moiety fused to thethiazolyl group to which they are attached, thus forming a fused ringsystem, said fused ring system being optionally substituted by one ormore group(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,alkoxy, haloalkoxy or hydroxyl; and X⁵ is O or S, or N—R³⁶ wherein R³⁶is H or C1-C3 alkyl; and Ar⁷ is a heterocyclyl, aryl or heteroarylgroup, each of which being optionally substituted by one or moregroup(s) selected from halo, cyano, alkyl, haloalkyl, cyclopropyl,alkoxy, haloalkoxy, aryl or hydroxyl; and X⁶ is O, S or N—R^(36′)wherein R^(36′) is H or C1-C3 alkyl; and R^(14′) is H or methyl; and R³⁴is H, alkyl, alkoxyalkyl, hydroxyalkyl, alkoxycarbonylaminoalkyl; andR³⁵ is H, alkyl, alkoxyalkyl, hydroxyalkyl, alkoxycarbonylaminoalkyl;and wherein, in formula If-1 when: R¹ is H, and Ar¹ is a 6-membered aryloptionally substituted by one or more group(s) selected from halo,cyano, C1-C3 alkyl, C1-haloalkyl, and R¹¹, R¹², R^(12′) and R¹³ areindependently selected from H, halo, C1-C3 alkyl, hydroxyl, methoxy, orR¹² together with R¹¹ or R¹³ forms an aryl or heterocyclyl or heteroarylmoiety fused to the pyridyl group to which they are attached and beingoptionally substituted by one or more group(s) selected from halo, C1-C3alkyl, methoxy or hydroxyl, then, Ar¹ is phenyl, 3-halophenyl,4-halophenyl, 2,3-dichlorophenyl, 3,4-dihalophenyl, 3,4,5-trihalophenyl,4-cyanophenyl, 4-(C1-C3 alkyl)phenyl, 4-(C1 haloalkyl)phenyl, and R¹¹,R¹², R^(12′) and R¹³ together with the pyridyl group they are attachedform a quinolin-2-yl, isoquinolin-3-yl or 8-haloquinolin-2-yl moiety;and in formula If-4 when: R¹ is H, and Ar¹ is a 6-membered aryloptionally substituted by one or more group(s) selected from halo,cyano, C1-C3 alkyl, C1-haloalkyl, and R¹⁷ together with R¹⁶ forms acycloalkyl or aryl moiety fused to the thiazolyl group to which they areattached, thus forming a fused ring system, said fused ring system beingoptionally substituted by one or more group(s) selected from halo, C1-3alkyl, methoxy or hydroxyl, then Ar¹ is phenyl, 3-halophenyl,4-halophenyl, 2,3-dichlorophenyl, 3,4-dihalophenyl, 3,4,5-trihalophenyl,4-cyanophenyl, 4-(C1-C3 alkyl)phenyl, 4-(C1 haloalkyl)phenyl, and R¹⁷and R¹⁶ form together with the thiazolyl group to which they areattached a benzothiazol-2-yl or 4,5,6,7-tetrahydro-1,3-benzothiazol-2-ylmoiety.
 23. The medicament according to claim 22 comprising a compoundselected from formulae Ig-1, Ig-2, Ig-3, Ig-4, Ig-5, Ig-6, Ig-7 and Ig-8

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein a depicts the bond linking R¹ to the piperazinemoiety; and Ar¹, R¹, X¹ and X² are as defined in claim 18; and R¹⁴,R^(14′), R¹⁵, R³⁴, R³⁵, X³, X⁵ and X⁶ are as defined in claim 22; andR^(12′) and R¹³ are independently selected from H, halo, cyano, alkyl,hydroxyalkyl, haloalkyl, cycloalkyl, heteroalkyl, hydroxyl, alkoxy,haloalkoxy, carboxy, alkoxycarbonyl, alkylcarbonyloxy,alkylcarbonylamino, haloalkylcarbonylamino, acylamino, carbamoyl,alkylcarbamoyl, carbamoylalkyl, carbamoylamino, alkylcarbamoylamino,alkylsulfonyl, haloalkylsulfonyl, sulfamoyl, alkylsulfamoyl,alkylsulfonylamino, haloalkylsulfonylamino, or R¹³ together with R^(12′)forms an alkylenedioxy group or a haloalkylenedioxy group, each of saidgroups being optionally substituted by one or more group(s) selectedfrom halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl or oxo;and R¹⁸, R¹⁹, R^(19′) and R²⁰ are independently selected from H, halo,cyano, alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy; and R²¹,R^(21′), R²², R^(22′) and R²³ are independently selected from H, halo,cyano, alkyl, haloalkyl, cyclopropyl, heterocyclyl optionallysubstituted by alkyl, hydroxyl, alkoxy, haloalkoxy, hydroxyalkoxy,alkylamino, alkylsulfonylamino, aminoalkoxy, alkoxycarbonylaminoalkoxy;and R²⁴, R^(24′), R²⁵, R^(25′) and R²⁶ are independently selected fromH, halo haloalkyl, cyclopropyl; and R²⁷, R²⁸, R²⁹ and R³⁰ areindependently selected from H, halo, cyano, alkyl, haloalkyl,cyclopropyl, alkoxy, haloalkoxy; and R^(27′), R^(28′), R^(29′) andR^(30′) are absent, or R^(27′), R^(28′), R^(29′) and R^(30′) are H underthe condition that R²⁸, R²⁹ and R³⁰ are H and that R²⁷ is selected fromH, chloro or fluoro; and the two bonds represented by the dotted linesin formula Ig-4 are both absent, or both present under the conditionthat R^(27′), R^(28′), R^(29′) and R^(30′) are absent; and R³¹, R^(31′),R³², R^(32′) and R³³ are independently selected from H, halo, cyano,alkyl, haloalkyl, cyclopropyl, alkoxy, haloalkoxy; and wherein, informula Ig-1 when: R¹ is H, and Ar¹ is a 6-membered aryl optionallysubstituted by one or more group(s) selected from halo, cyano, C1-C3alkyl, C1-haloalkyl, and R^(12′), R¹³, R¹⁸, R¹⁹, R^(19′) and R²⁰ areindependently selected from H, halo, C1-3 alkyl, hydroxyl, methoxy,then, Ar¹ is phenyl, 3-halophenyl, 4-halophenyl, 2,3-dichlorophenyl,3,4-dihalophenyl, 3,4,5-trihalophenyl, 4-cyanophenyl, 4-(C1-C3alkyl)phenyl, 4-(C1 haloalkyl)phenyl, and R^(12′), R¹³, R¹⁸, R¹⁹,R^(19′) and R²⁰ are H, or R^(12′), R¹³, R¹⁹, R^(19′), R²⁰ are H and R¹⁸is fluoro, chloro, and in formula Ig-4 when R¹ is H, and Ar¹ is a6-membered aryl optionally substituted by one or more group(s) selectedfrom halo, cyano, C1-C3 alkyl, C1-haloalkyl, and R²⁷, R²⁸, R²⁹ and R³⁰are independently selected from H, halo, C1-3 alkyl, methoxy, andR^(27′), R^(28′), R^(29′) and R^(30′) are absent or H under thecondition that R²⁸, R²⁹ and R³⁰ are H and R²⁷ is selected from H, chloroor fluoro, then Ar¹ is phenyl, 3-halophenyl, 4-halophenyl,2,3-dichlorophenyl, 3,4-dihalophenyl, 3,4,5-trihalophenyl,4-cyanophenyl, 4-(C1-C3 alkyl)phenyl, 4-(C1 haloalkyl)phenyl, and R²⁷,R²⁸, R²⁹ and R³⁰ are H, and R^(27′), R^(28′), R^(29′) and R^(30′) areabsent or H under the condition that R²⁷, R²⁸, R²⁹ and R³⁰ are H. 24.The medicament according to claim 22 comprising a compound havingformula Ih-2

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein a designates the bond linking R¹ to the piperazinemoiety; and Ar¹, R^(1′), X¹ and X² are as defined in claim 18; and X³ isas defined in claim 22; and R^(14″) is H or methyl; and X⁴ is O, CH₂,CF₂, C(CH₃)₂, N—(C1-C3 alkyl)N-phenyl; and R^(36a), R^(36b), R^(36′a),R^(37a) and R^(37′a) are independently selected from H, C1-C3 alkyl,alkoxyC1-C3 alkyl.
 25. The medicament according to claim 19 comprising acompound selected from formulae Ii-1, Ii-2, Ii-3, Ii-4, Ii-5, Ii-6,Ii-7, Ii-8, Ij-1, Ij-2, Ij-3, Ij-4, Ij-5, Ij-6, Ij-7, Ij-8, Ik-1, Ik-2,Ik-3, Ik-4, Ik-5, Ik-6, Ik-7, Ik-8, Ii′-1, Ii′-2, Ii′-3, Ii′-4, Ii′-5,Ii′-6, Ii′-7 and Ii′-8

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein a depicts the bond linking R¹ to the piperazinemoiety; and R¹, X¹ and X² are as defined in claim 18; and Ar⁴, R⁴,R^(4′), R⁵, R^(5′), R⁶, R⁷, R^(7′), M¹, M² are as defined in claim 20;and Ar⁵, Ar⁶, Ar⁷, R¹¹, R¹², R^(12′), R¹³, R¹⁴, R^(14′), R¹⁵, R¹⁶, R¹⁷,R³⁴, R³⁵, X³, X⁵, X⁶, and are as defined in claim
 22. 26. The medicamentaccording to claim 25 comprising a compound selected from formulae Il-1,Il-2, Il-3, Il-4, Il-5, Il-6, Il-7, Il-8, Il′-1, Il′-2, Il′-3, Il′-4,Il′-5, Il′-6, Il′-7, Il′-8

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein: a depicts the bond linking R¹ to the piperazinemoiety; and R¹, X¹ and X² are as defined in claim 18; and R⁴, R^(4′),R⁵, R^(5′), R⁶, M¹ and M² are as defined in claim 20; and R^(12′), R¹³,R¹⁴, R^(14′), R¹⁵, R¹⁸, R¹⁹, R^(19′), R²⁰, R²¹, R^(21′), R²², R^(22′),R²³, R²⁴, R^(24′), R²⁵, R^(25′), R²⁶, R²⁷, R^(27′), R²⁸, R^(28′), R²⁹,R^(29′) R³⁰, R^(30′), R³¹, R^(31′), R³², R^(32′), R³³, R³⁴, R³⁵, X³, X⁵;X⁶; and the two bonds represented by the dotted lines are as defined inclaim
 23. 27. The medicament according to claim 26 comprising a compoundselected from formulae Im-1, Im-2, Im-3, Im-4, Im-5, Im-6, Im-7, Im-8,Im′-1, Im′-2, Im′-3, Im′-4, Im′-5, Im′-6, Im′-7 and Im′-8

or a pharmaceutically acceptable salt or solvate thereof and at leastone pharmaceutically acceptable carrier, diluent, excipient and/oradjuvant, wherein: a designates the bond linking R¹ to the piperazinemoiety; and R¹, X¹ and X² are as defined in claim 18; and R⁵, R⁶, M¹ andM² are as defined in claim 21; and R^(12′), R¹³, R¹⁴, R^(14′), R¹⁵, R¹⁸,R¹⁹, R^(19′) R²⁰, R²¹, R^(21′), R²², R^(22′), R²³, R²⁴, R^(24′), R²⁵,R^(25′) R²⁶, R²⁷, R^(27′), R²⁸, R^(28′), R²⁹, R^(29′), R³⁰, R^(30′),R³¹, R^(31′), R³², R^(32′), R³³, R³⁴, R³⁵, X³, X⁵, X⁶; and the two bondsrepresented by the dotted lines are as defined in claim
 23. 28. Themedicament according to claim 17 comprising at least onepharmaceutically acceptable carrier, diluent, excipient and/or adjuvantand a compound selected from the group consisting of:(3-(4-chlorophenyl)-1H-pyrazol-5-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(3,4-dichlorophenyl)-1H-pyrazol-5-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(pyridin-2-yl)-5,6-dihydro-triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(5-chloropyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2,4-dichlorophenyl)-1H-pyrazol-5-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(isoquinolin-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-yl)methanone;(3-(4-phenoxyphenyl)-1H-pyrazol-5-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(8-fluoroquinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(8-chloroquinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(3-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(6-phenylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-(3-(trifluoromethyl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(2-(2,3-dichlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(2-(4-chlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-(piperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-(4-phenylpiperazin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2,4-dichlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(2-(3,5-dichlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(3-(6-(pyrrolidin-1-yl)pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(6-morpholinopyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(6-(trifluoromethyl)pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(3,4-dimethoxyphenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(8-(4-fluorophenyl)-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(3-chlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(8-isopropyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-phenyloxazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(8-methyl-3-(2-phenyloxazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(8-methyl-3-(2-phenyloxazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(2-phenyloxazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(8-(2-hydroxyethyl)-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4′-fluoro-[1,1′-biphenyl]-4-yl)(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(4-phenylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2-chlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(benzo[d]thiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(8,8-dimethyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-3-yl)phenyl)methanone;(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-3-yl)phenyl)methanone;(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2-chlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(2-chlorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(3-(2-(4-chlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(quinolin-2-yl)-5,6-dihydro-[I1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(8-methyl-3-(4-methyl-2-phenylthiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2-chlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(8-methyl-3-(4-methyl-2-phenylthiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;naphthalen-1-yl(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)(3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(8-methyl-3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(8-methyl-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-(3-(2-(4-fluorophenyl)oxazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;2-(7-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)quinoline;2-(4-fluorophenyl)-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)ethanone;(5-phenylpyridin-2-yl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(6-phenylpyridin-3-yl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(2-phenylpyrimidin-5-yl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-phenylcyclohexyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;cyclohexyl(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;3-methyl-1-(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)butan-1-one;[1,1′-biphenyl]-2-yl(3-(quinolin-2-yl)-5,6-dihydro-triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(furan-3-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(pyrimidin-5-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(9-methyl-9H-carbazol-2-yl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(pyrimidin-2-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(pyrazin-2-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(pyridazin-3-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;4′-(3-(quinolin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-[1,1′-biphenyl]-4-carbonitrile;1-(4-(3-(quinolin-2-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)phenyl)piperidin-2-one;(4-morpholinophenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)(3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-fluorophenyl)thiazol-4-yl)-6-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4-fluorophenyl)thiazol-4-yl)-5-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3,4-dichlorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3,4-difluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-chloro-4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-chloro-3-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(3,4,5-trifluorophenyl)methanone;(8-methyl-3-(2-phenyloxazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(6-phenylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(R)-(3-(2-(2,3-dichlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(2-(4-phenylpiperazin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(3-(2-(2,4-dichlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(R)-(3-(2-(3-chlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(2-phenyloxazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(2-phenyloxazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(4-fluorophenyl)(8-(2-hydroxyethyl)-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(4′-fluoro-[1,1′-biphenyl]-4-yl)(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-(4-fluorophenyl)(8-methyl-3-(4-phenylthiazol-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(3-(2-(2-chlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(R)-(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-3-yl)phenyl)methanone;(R)-(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-(3-(2-(2-chlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-[1,1′-biphenyl]-4-yl(3-(2-(2-chlorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-[1,1′-biphenyl]-4-yl(8-methyl-3-(4-methyl-2-phenylthiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-[1,1′-biphenyl]-4-yl(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-[1,1′-biphenyl]-4-yl(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(S)-(4-fluorophenyl)(8-methyl-3-(pyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(4′-fluoro-[1,1′-biphenyl]-4-yl)(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(4-fluorophenyl)(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(8-methyl-3-(quinolin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(S)-(4-fluorophenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(4-fluorophenyl)(8-methyl-3-(2-phenylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(R)-(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2,4-difluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(5-phenyl-1H-1,2,4-triazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(5-phenyl-1H-1,2,4-triazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(2-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(2-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(2-(2-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(3-(2,4-difluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;[1,1′-biphenyl]-4-yl(3-(2-((4,5-dichloro-1H-imidazol-1-yl)methyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-((4,5-dichloro-1H-imidazol-1-yl)methyl)thiazol-4-yl)-5,6-dihydro-[I1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4′-fluoro-[1,1a′-biphenyl]-4-yl)methanone;(3-(2-(4-chlorobenzyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(2-(4-chlorobenzyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(p-tolyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(thiophen-2-yl)phenyl)(3-(2-(p-tolyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(p-tolyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-(thiophen-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-(thiophen-2-yl)phenyl)(3-(2-(thiophen-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(thiophen-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(2-(thiophen-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(((4-chlorophenyl)sulfonyl)methyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(((4-chlorophenyl)sulfonyl)methyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(((4-chlorophenyl)sulfonyl)methyl)thiazol-4-yl)-5,6-dihydro-triazolo[4,3-a]pyrazin-7(8H)-yl)(4′-fluoro-[1,1′-biphenyl]-4-yl)methanone;(4-fluorophenyl)(3-(2-(2-methoxyphenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2-methoxyphenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;[1,1′-biphenyl]-4-yl(3-(2-(2-methoxyphenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;[1,1′-biphenyl]-4-yl(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-(3-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(3-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(3-phenyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(3-phenyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-bromophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4-bromophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(5-methylthiophen-2-yl)phenyl)methanone;4-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)benzonitrile;[1,1′-biphenyl]-4-yl(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(2-(pyridin-4-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(quinolin-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4-(dimethylamino)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4′-fluoro-[1,1′-biphenyl]-4-yl)(3-(3-phenyl-1,2,4-oxadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(pyridin-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(pyrimidin-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(S)-(8-methyl-3-(2-morpholinothiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(pyridin-4-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4-(dimethylamino)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(pyridin-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(2-methylthiophen-3-yl)phenyl)methanone;(R)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(2-methylthiophen-3-yl)phenyl)methanone;(3-(2-(pyrazin-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;4-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)benzonitrile;(4-fluorophenyl)(3-(2-(pyrazin-2-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(3-(1-methyl-5-phenyl-1H-pyrazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-morpholinophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(4-morpholinophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-(4-methylpiperazin-1-yl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(4-(4-methylpiperazin-1-yl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-(piperidin-1-yl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(4-(piperidin-1-yl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(4-(pyrrolidin-1-yl)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(piperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(pyrrolidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(pyrrolidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(1-methyl-2-phenyl-1H-imidazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-(dimethylamino)phenyl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(1-(2-methoxyethyl)-3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(1-(2-methoxyethyl)-3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-isobutylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2-(2-methoxyethyl)morpholino)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(3-(2-(2,5-dimethylmorpholino)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2-hydroxyphenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2,6-dimethylmorpholino)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2,2-dimethylmorpholino)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(3-methylthiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(R)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(3-methylthiophen-2-yl)phenyl)methanone;(4-fluorophenyl)(3-(2-(2-hydroxyphenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(S)-(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(3-methylthiophen-2-yl)phenyl)methanone;(3-(2-(2-methylmorpholino)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4,4-dimethylpiperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(5-methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(4,4-dimethylpiperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;(4-fluorophenyl)(3-(2-(2-(methoxymethyl)piperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(4-fluorophenyl)(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(2-(2-(methoxymethyl)piperidin-1-yl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;tert-butyl(2-(2-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenoxy)ethyl)carbamate;(3-(2-(2-(2-hydroxyethoxy)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2-(2-aminoethoxy)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;N-(4-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenyl)methanesulfonamide;(3-(1-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(1-(2-hydroxyethyl)-5-phenyl-1H-pyrazol-3-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;[1,1′-biphenyl]-4-yl(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(8-methyl-3-(6-methylpyridin-2-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(2,4-difluorophenyl)-5-methylthiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(3-(dimethylamino)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(3-(dimethylamino)phenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-fluorophenyl)methanone;N-(3-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenyl)methanesulfonamide;N-(2-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)phenyl)methanesulfonamide;(3-(4-chlorophenyl)-1H-pyrazol-5-yl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(3-(3,4-dichlorophenyl)-1-methyl-1H-pyrazol-5-yl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;(5-(4-chlorophenyl)-1-methyl-1H-pyrazol-3-yl)(3-(2-(4-fluorophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone;tert-butyl(2-(3-phenyl-5-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate;tert-butyl(2-(5-phenyl-3-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate;(3-(2-(2-bromophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;(3-(2-(3-bromophenyl)thiazol-4-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(thiophen-2-yl)phenyl)methanone;2-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)benzonitrile;3-(4-(7-(4-(thiophen-2-yl)benzoyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)thiazol-2-yl)benzonitrile;(3-(2-(4-fluorophenyl)thiazol-4-yl)-8-methyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)(4-(2-methylthiophen-3-yl)phenyl)methanone.and pharmaceutically acceptable salts and solvates thereof.
 29. A methodfor suppressing the LH-surge in assisted conception in a patientcomprising administering to said patient a compound of formula I asdefined in claim 17 or a pharmaceutically acceptable salt or solvatethereof in an amount sufficient to suppress said LH-surge.
 30. A methodfor causing male castration and inhibiting the sex drive in mencomprising administering to said patient a compound of formula I asdefined in claim 17 or a pharmaceutically acceptable salt or solvatethereof in an amount sufficient to cause castration.